Review Article Immature Dentate Gyrus: An Endophenotype of...

Hindawi Publishing CorporationNeural PlasticityVolume 2013 Article ID 318596 24 pageshttpdxdoiorg1011552013318596

Review ArticleImmature Dentate Gyrus An Endophenotype ofNeuropsychiatric Disorders

Hideo Hagihara12 Keizo Takao123 Noah M Walton4

Mitsuyuki Matsumoto4 and Tsuyoshi Miyakawa123

1 Division of Systems Medical Science Institute for Comprehensive Medical Science Fujita Health University1-98 Dengakugakubo Kutsukake-cho Toyoake Aichi 470-1192 Japan

2 CREST Japan Science and Technology Agency 4-1-8 Honcho Kawaguchi Saitama 332-0012 Japan3 Section of Behavior Patterns Center for Genetic Analysis of Behavior National Institute for Physiological Sciences5-1 Aza-Higashiyama Myodaiji-cho Okazaki Aichi 444-8787 Japan

4CNS Astellas Research Institute of America LLC 8045 Lamon Avenue Skokie IL 60077 USA

Correspondence should be addressed to Tsuyoshi Miyakawa miyakawafujita-huacjp

Received 5 March 2013 Revised 17 April 2013 Accepted 19 April 2013

Academic Editor Chitra D Mandyam

Copyright copy 2013 Hideo Hagihara et alThis is an open access article distributed under the Creative CommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Adequate maturation of neurons and their integration into the hippocampal circuit is crucial for normal cognitive function andemotional behavior and disruption of this process could cause disturbances in mental health Previous reports have shown thatmice heterozygous for a null mutation in 120572-CaMKII which encodes a key synaptic plasticity molecule display abnormal behaviorsrelated to schizophrenia and other psychiatric disorders In these mutants almost all neurons in the dentate gyrus are arrested at apseudoimmature state at the molecular and electrophysiological levels a phenomenon defined as ldquoimmature dentate gyrus (iDG)rdquoTo date the iDG phenotype and shared behavioral abnormalities (including working memory deficit and hyperlocomotor activity)have been discovered in Schnurri-2 knockout mutant SNAP-25 knock-in and forebrain-specific calcineurin knockout mice Inaddition both chronic fluoxetine treatment and pilocarpine-induced seizures reverse the neuronal maturation resulting in theiDG phenotype in wild-type mice Importantly an iDG-like phenomenon was observed in post-mortem analysis of brains frompatients with schizophreniabipolar disorder Based on these observations we proposed that the iDG is a potential endophenotypeshared by certain types of neuropsychiatric disordersThis review summarizes recent data describing this phenotype and discussesthe datarsquos potential implication in elucidating the pathophysiology of neuropsychiatric disorders

1 Introduction

The exact mechanisms within the brain that underlie mostpsychiatric disorders remain largely unknown and one ofthe major challenges in psychiatric research is to identifythe pathophysiology in the brains of patients with thesedisorders This is challenging because psychiatric disordersare diagnosed on the basis of behavioral characteristics andnot biological criteria Therefore each psychiatric disorderlikely consists of multiple biologically heterogeneous popu-lations which further complicates the search for underlyingpathophysiologies

Previously studies have identified the ldquoimmature dentategyrus (iDG)rdquo a potential brain endophenotype shared by

several psychiatric disorders including schizophrenia andbipolar disorder The iDG was identified in animal modelsof psychiatric disorders which were selected using large-scale behavioral screening of genetically engineered mice[1] In the iDG phenotype most of the granule cells orprincipal neurons in the dentate gyrus (DG) within thehippocampus are arrested at a pseudoimmature status inwhich the molecular and physiological properties are similarto those of normal immature neurons from the DG To datethe iDG phenotype has been identified in several strains ofmutant mice including 120572-CaMKII heterozygous knockout(HKO) mice [1] Schnurri-2 (Shn-2) knockout (KO) mice[2] mutant SNAP-25 knock-in (KI) mice [3] and forebrain-specific calcineurin (CN) KO mice [4] A signature pattern

2 Neural Plasticity

Body weight

Rectal temperature

Grip strength

Anxiety-like behaviorActivity

Motor coordinationPain sensitivity

Prepulse inhibition

Depression-like behaviorWorking memory

Reference memory

Social interaction(novel environment)

Social interaction(home cage)

Increased 119875 lt 0001Increased 119875 lt 001

Increased 119875 lt 005

Decreased 119875 lt 005



Figure 1 Heat map showing behavioral phenotypes of more than 160 strains of genetically engineered mice Each column represents themouse strain analyzed in the laboratory of the authorrsquos group (unpublished data) Each row represents a behavior category assessed by thecomprehensive battery of behavioral tests Colors represent an increase (red) or decrease (green) compared between wild-type and mutantmice Adapted from Takao et al [8]

quite similar to the iDG phenotype identified in thesemutantmice has also been found in mice treated with chronicfluoxetine [5] and in a pilocarpine-induced mouse model ofepilepsy [6] Moreover postmortem analysis for molecularmarkers of neuronal maturity in the DG revealed an iDG-like signature for brains of patients with schizophrenia andbipolar disorder [7]

The purpose of this review is to introduce how theiDG phenotype was identified and its molecular and cellularsignature An additional goal is to summarize potentialmechanisms underlying the iDG phenotype and its impacton brain functions

2 Discovery of iDG in 120572-CaMKII HKO Mice

A high-throughput comprehensive behavioral testing batterywas developed for many different strains of geneticallyengineered mice The battery of tests covers many behavioraldomains ranging from sensorimotor functions to highlycognitive functions like learning and memory In the courseof a large-scale effort to phenotype the genetically engineeredmice (mutant mice) this battery of tests was administeredto more than 160 strains of knockout and transgenic mice(Figure 1) [8] Surprisingly when tested most of the strains ofmutant mice displayed at least some aberrant behavioral phe-notypes whichmay suggest that many of the genes expressedin the brain may have some functional significance at thebehavior level In the course of screening the mutant micepopulations a number of mouse strains were identified thatshowed abnormal behaviors common to neuropsychiatricdisorders (eg schizophrenia bipolar disorder and autism)Among these mutant mouse models the 120572-CaMKII HKOmice showed a particularly dramatic series of abnormalbehaviorsThe first discovery of the iDG phenotype occurredduring investigations into the neuropathophysiology under-lying these behaviors

Calmodulin-dependent protein kinase II (CaMKII) isa major downstream molecule of the N-methyl-d-asparticacid (NMDA) receptor which has presumed involvement inthe pathophysiology of schizophrenia The function of theNMDA receptor can bemodulated by calcineurin a potentialsusceptibility gene we previously identified [9 10] CaMKII isthought to play an essential role in neural plasticity such aslong-term potentiation and long-term depression [11]

Perhaps the most striking behavioral phenotype of 120572-CaMKII HKO mice is that they occasionally kill their cagemates (often littermates) Prior to 6months of age120572-CaMKIIHKO mice kill more than half of their group-housed cagemates In addition these mice show greatly increased loco-motor activity in the open field test While 120572-CaMKII HKOmice demonstrate normal reference memory as assessed bythe reference memory version of the eight-arm radial mazetest their working memory is severely impaired Likewisein the T-maze forced-alternation test the working memoryof the 120572-CaMKII HKO mice was found to be severelyimpaired while they showed normal performance in a simpleleftright discrimination task using the same apparatusesPrevious studies have presented representative videos of theperformance of 120572-CaMKII HKO mice in these tasks [12]Using the home cage locomotor activity monitoring systemwhich measures distance travelled in the home cage it wasshown that the locomotor activity patterns of the 120572-CaMKIIHKO mice slowly and dramatically change over time Thesemice show a periodic mood-change-like behavior in theirhome cage (Figure 2(a)) and 1 cycle lasts approximately 10ndash20 d The manifestations of this behavioral phenotype are soclear that these mutant mice can be easily identified usingthese activity patterns

The next task was to understand the underlying patho-physiology in the brains of the 120572-CaMKII mutants thatshow this dramatic array of behavioral abnormalities Firsta transcriptome analysis of the hippocampus of mutant mice

Neural Plasticity 3

Time (day)

Dist

ance

trav

eled

(au

)

0

400

0

400

0

400

5 10 15 20 25 30 35

40 45 50 55 60 65

75 80 85 90Time (day)

Dist

ance

trav

eled

(au

)

0

400

0

400

0

400

5 10 15 20 25 30 35

40 45 50 55 60 65 70

75 80 85 90

Wild-type

Light periodDark period


70

120572-CaMKII HKO

(a)

Tryptophan 23-dioxygenase Desmoplakin Interleukin 1 receptor type1

Nephronectin

Wild-type120572-CaMKII HKO



Pregnancy upregulated nonubiquitouslyexpressed CaM kinase

Solute carrier family 39 (metal iontransporter) member 6

Relat

ive e

xpre

ssio

nRe

lativ

e exp

ress

ion

Relat

ive e

xpre

ssio

nRe

lativ

e exp

ress

ion

Relat

ive e

xpre

ssio

nRe

lativ

e exp

ress

ion

543210

56

43210

2

15

1

05

0

2

15

1

05

0

15

1

05

0

08

06

04

02

0

(b)

Late progenitorimmature neuron Immature neuron Mature neuron

PSA-NCAM Calretinin

PSA-NCAM Calretinin

Calbindin

Calbindin

120572-CaMKII HKO

Wild-type

(c)

120572-CaMKII HKOWild-typeCalbindinArc-dVenus

200 120583m

(d)

Figure 2 Mood-change-like behavior and the iDG phenotype in 120572-CaMKII HKO mice (a) Pattern of locomotor activity of wild-type and120572-CaMKII HKO mice in their home cage Mutant mice were hyperactive and showed a periodic mood-change-like activity pattern AUarbitrary unit (b) Among the downregulated genes in the hippocampus of 120572-CaMKII HKOmice several genes were expressed selectively inthe DG (Allen Brain Atlas [42] Seattle WA Allen Institute for Brain Science copy 2004ndash2008 Available from httpwwwbrain-maporg)Graphs indicate the relative expression levels of each gene in the microarray experiment (c) In 120572-CaMKII HKO mice expression ofPSA-NCAM (a late-progenitor and immature-neuron marker) and calretinin (an immature neuron marker) was markedly increased andexpression of calbindin (a mature neuron marker) was decreased (d) Expression of Arc-dVenus in the DG of 120572-CaMKII HKOmice after theworking memory task (eight-arm radial maze test) was completely abolished Red calbindin green Arc-dVenus Adapted from Yamasaki etal [1] and Matsuo et al [13]

4 Neural Plasticity

was conducted Gene expression in 120572-CaMKII HKO micewas highly dysregulated with altered expressions of morethan 2000 genes in the hippocampus of themutants Surpris-ingly of the top 30 hippocampal genes with downregulatedexpression in 120572-CaMKII mutants 6 genes showed highlyselective expression in the DG (Figure 2(b)) These dataimplied the existence of some unknown abnormalities in theDG of these mutants

Adult neurogenesis was then examined and a largeupregulation (gt50) of neurogenesis was demonstratedin 120572-CaMKII mutant mice Traditionally the process ofadult neurogenesis involves a recapitulation during whichstemprogenitor cells give way to immature postmitoticneurons which then mature to adopt distinct morphologicaland physiological properties in the hippocampus Basedon the observed upregulation of adult neurogenesis in the120572-CaMKII mutant mice it was interesting to determinewhether the 120572-CaMKII mutant mice followed the traditionalpath of neurogenesis Gene chip analysis of hippocampusdemonstrated a reduced expression of the gene for calbindina marker for mature neurons in the DG in the mutantsFurthermore calbindin as assessed by immunohistochem-istry was dramatically reduced in the DG of the 120572-CaMKIImutants (Figure 2(c)) In addition expression of calretinina marker for immature neurons in the DG was increasedas was expression of polysialylated neuronal cell adhesionmolecule (PSA-NCAM) a marker for late progenitor cellsand immature neurons Taken together these findings sug-gest that in 120572-CaMKII mutant mice the number of immatureneurons are upregulated and the number of mature neuronsare downregulated

Golgi staining was also performed to examine the mor-phology of the DG neurons Interestingly staining of theDG was difficult to achieve in the 120572-CaMKII mutant micepresenting a challenge in the quantification of morphologicalalterations Fewer dendritic intersections and shorter overalldendritic length were demonstrated in the 120572-CaMKIImutantmice consistent with the idea that DG neurons in these miceare immature

Moreover DG neurons in the 120572-CaMKII mutant micewere found to have many electrophysiological features thatare known characteristics of immature dentate neuronsincluding high input resistance and a decreased number ofspikes during sustained depolarizationThis finding indicatesthat in the 120572-CaMKII mutant mice most of the DG neuronshave electrophysiological properties consistent with thoseof immature neurons Interestingly 120572-CaMKII HKO micealso exhibit abnormal synaptic transmissionplasticity atmossy fiber-CA3 synapses Specifically 120572-CaMKII mutantmice have increased basal transmission and dramaticallydecreased facilitation at these synapses

The 120572-CaMKII HKO mice were mated with transgenicmice expressing destabilized Venus (dVenus) under the Arcpromoter Arc is known to be induced by neural activity Innormal mice a number of hippocampal neurons (includingDG neurons) become positive for Arc-dVenus after per-forming working memory tasks (Figure 2(d)) In 120572-CaMKIIHKO mice Arc-dVenus expression is almost completelyabolished in the DG after performing a working memory

task suggesting that the DG in these mutants is not fullyfunctional [13]

These experiments were the first to demonstrate thatthe most of the DG neurons in 120572-CaMKII HKO mice arearrested at a pseudoimmature status This arrest of maturitywas termed the ldquoimmature dentate gyrus (iDG)rdquo phenotype

3 iDG Is an Endophenotype Shared byGenetically Engineered Mice withAbnormal Behaviors Characteristic forNeuropsychiatric Disorders

After identification of the iDG phenotype it was impor-tant to investigate whether other strains of mutant miceshare this phenotype Over the past 10 years the behav-iors of mutant mice have been assessed continuouslyusing the comprehensive behavioral test battery previouslydescribed [8] The majority of the behavioral phenotypesreported are registered in the mouse phonotype database(httpwwwmousephenotypeorg) This database was usedto identify strains of mice that exhibited behavioral pheno-type(s) similar to that shownby the120572-CaMKIImutantsMorethan 160 different strains of mutant mice were investigatedand the best behavioral match was identified in a strain of themice lacking a transcription factor called Schnurri-2 (Shn-2KO mice) [2]

Shn-2KOmice show an array of behavioral abnormalitiesthat is quite similar to those of 120572-CaMKII HKO miceincluding hyperlocomotor activity and severe deficits inworking memory In Shn-2 KO mice locomotor activityis dramatically increased and prepulse inhibition (PPI) isimpaired [2]However Shn-2KOmice have normal referencememory as assessed by the left-right discrimination taskperformed in a T-maze In addition the Shn-2 KOmice haveseverely impaired working memory as suggested by theirperformance in the T-maze forced-alternation task and theeight-arm radial maze (Figures 3(a)ndash3(d)) [2]

To identify the pathophysiologic abnormalities responsi-ble for the behavioral phenotypes in Shn-2 KOmice an addi-tional gene chip analysis was conducted and the hippocampaltranscriptome patterns of Shn-2 KO mice were compared tothose of 120572-CaMKII HKO mice Remarkably the 2 mutantstrains showed strikingly similar gene expression patterns inthe hippocampus (Figures 4(a) and 4(b)) with expressionof gt100 genes altered in a similar manner with regard toboth the direction and the magnitude of the alterations Forexample as observed in 120572-CaMKII HKO mice calbindinexpression was dramatically decreased in the DG of Shn-2KOmice (Figure 4(c)) [2]Whole-cell patch recordingsmadefrom granule cells in the DG revealed that DG neurons inShn-2 KO mice have electrophysiological features shown byimmature neurons such as a lower current threshold forfiring a short latency to the first spike and a decreasednumber of spikes during sustained depolarization [2] Thisevidence supports the conclusion that Shn-2 KO mice alsoexpress iDG phenotype Additional strains of mutant micewith the iDG phenotype have also been identified

Neural Plasticity 5

Eight-arm radial maze test

4

5

6

7

8

3 6 9 12Blocks of 2 trials

Diff

eren

t arm

choi

ce in

firs

t 8 en

trie

s

lowastlowast

lowast

lowastlowast

lowast lowast lowast

Wild-type (119899 = 16)Shn-2 KO (119899 = 10)

(a)


Blocks of 2 trials

0

5

10

15

20

25

3 6 9 12

lowast lowast

lowast lowastlowast

lowast lowast

Revi

sitin

g er

rors

Wild-type (119899 = 16)Shn-2 KO (119899 = 10)

(b)

T-maze test

50

60

70

80

90

100

02 4 6 8

Cor

rect

resp

onse

s (

)

Sessions

lowast lowastlowast

Wild-type (119899 = 16)Shn-2 KO (119899 = 7)

(forced-alternation task)

(c)

0

20

40

60

80

100

2 4 6 8 10 12 14Sessions

T-maze test(left-right discrimination task)

Reversal

Cor

rect

resp

onse

s (

)

Wild-type (119899 = 16)Shn-2 KO (119899 = 5)

(d)

Figure 3 Impairedworkingmemory performance in Shn-2KOmice (a) In the spatial workingmemory version of the eight-arm radialmazecompared to controls Shn-2 KOmice performed significantly worse with respect to the number of different arm choices in the first 8 entries(genotype effect F

124=62104119875 lt 00001) (b)Mutantsmade significantlymore revisiting errors than controls (genotype effect F

124=45597

119875 lt 00001 genotypetimes trial block interaction F12228

= 1470119875 = 01345) (c) Shn-2KOmice also showedpoorworkingmemory performancein the T-maze forced-alternation task (genotype effect F

121= 20497 119875 = 00002 genotype times session interaction F

7147= 3273 119875 = 00029)

(d) Shn-2 KO and wild-type mice were comparable in the left-right discrimination task (genotype effect 119865119= 0209 119875 = 06529) and

reversal learning (genotype effect 119865119= 5917 119875 = 00251) Asterisks indicate statistical significance determined using the Studentrsquos 119905-test

with a correction for multiple comparisons in each block (a b) and each session (c) (lowast119875 lt 005) Adapted from Takao et al [2]

6 Neural Plasticity

0

1

2

3

4

5

0 1 2 3 4 5 6

120572-C

aMKI

I HKO

mic

e (fo

ld ch

ange

)

Shn-2 KO mice (fold change)

119903 = 081 (119875 lt 00001)

(a)

Wild-type

Normalized expression Normalized expression

Shn-2 KOWild-type

A130090K04RikWnk4

Ccnd1Fbxo7Unc5d

MGI1930803Spata13

LOC547362Nhlh1

Acvr1c

0 1 2 3 4 5

Ryr1Tspan18Pcdh21

Marcksl1

Capn3Calb1NpntDsp

Tdo2

0 05 1

0 1 2 3 4 5 6 7

0 05 1

120572-CaMKII HKO

1460043 at

(b)

Calbindin

Calretinin

Wild-type Shn-2 KO

Wild-type Shn-2 KO

500 120583m

250 120583m

(c)

Figure 4 Maturation abnormalities in DG neurons of Shn-2 KO mice (a) The hippocampal transcriptome pattern of Shn-2 KO mice issimilar to that of 120572-CaMKII HKOmice which also demonstratedmaturation abnormalities in the DG Genes showing differential expressionbetween genotypes at 119875 lt 0005 in both experiments were plotted (b) Normalized gene expression of differentially expressed genes in Shn-2KO and 120572-CaMKII HKO mice The top 10 genes are indicated in the graphs (c) Expression of the mature neuronal marker calbindin wasdecreased and the expression of the immature neuronal marker calretinin was markedly increased in the DG of Shn-2 KO mice Adaptedfrom Takao et al [2]

Synaptosomal-associated protein of 25 kDa (SNAP-25)regulates exocytosis of neurotransmitters and is thoughtto be involved in the neuropsychiatric disorders such asschizophrenia [14 15] attention-deficithyperactivity dis-order (ADHD) [16 17] and epilepsy [18 19] The iDG

phenotype was also identified in SNAP-25 knock-in (KI)mice with a single amino acid substitution [3] Behaviorallythese mice also show severe deficits in working memory Ofnote chronic administration of valproic acid an antiepilepticdrug rescued both the iDG phenotype and workingmemory

Neural Plasticity 7

deficit in SNAP-25 KI mice CN is a key signal transductionmolecule in the brain and several studies have suggested alink between dysfunction of CN signaling and schizophrenia[9 20] Conditional forebrain-specific CN KO mice alsoexhibit abnormal behaviors related to schizophrenia [10 21]including a severe working memory deficit and an iDGphenotype was also observed in CN KOmice [4]

Further studies have established a method for assessingthe existence of the iDG phenotype using real-time poly-merase chain reaction (PCR) with 3 probes (Figure 5) [22]selected using gene chip data from120572-CaMKIIHKOmiceThemolecular markers for iDG include increased expression ofdopamine receptor D1A (Drd1a) and decreased expression oftryptophan 23-dioxygenase (Tdo2) and desmoplakin (Dsp)in the DG of mutant mice [1] To date based on thesemolecular markers for iDG 9 of the 16 strains of micethat exhibited abnormal behaviors (eg hyperlocomotoractivity reduced anxiety-like behavior and impairedworkingmemory) have been shown to express the iDG phenotypeThese results suggest that iDG is a common endophenotypeshared by mice with behavioral abnormalities characteristicfor neuropsychiatric disorders

Furthermore the current results demonstrated that hip-pocampal gene expression patterns of mice expressing aconstitutively active cAMP-response element-binding pro-tein (CREB) variant (VP16-CREB) were similar to those of120572-CaMKII HKO Shn-2 KO or SNAP-25 KI mice NotablyVP16-CREB mice exhibited dramatic alteration in expres-sion of Calb1 Dsp glial fibrillary acidic protein (GFAP)and complement genes in the hippocampus [23] It hasbeen shown previously that CREB activation is observedin immature granule cells and plays important roles indifferentiation survival and maturation of neurons [24]Thus it is possible that chronic activation of CREB induceda maturation abnormality of the granule cells resulting in aniDG-like phenotype

4 Induction of iDG in Wild-Type Animals

The iDG phenotype can be seen not only in geneticallyengineered mice but also in properly manipulated wild-type normal mice For example Kobayashi et al found thatchronic treatment with the antidepressant fluoxetine (FLX)one of the most widely used selective serotonin reuptakeinhibitors (SSRI) can induce iDG phenotypes in adult mice[5] In FLX-treated mice expression of Calb1 Tdo2 and Dspmarkers for mature granule cells was greatly reduced inthe DG In contrast expression of calretinin a marker forimmature granule cells was increased in the DG [5] Thesefindings suggest that the number of immature granule cellsis upregulated and the number of mature granule cells isdownregulated in FLX-treated mice ElectrophysiologicallyFLX-treated granule cells showed higher excitability whichis a functional characteristic observed in immature granulecells FLX treatment was also found to reduce mossy fibersynaptic facilitation to juvenile levels [5] These molecularand electrophysiological phenotypes found in FLX-treatedmice are strikingly similar to those found in 120572-CaMKIIHKOShn-2 KO and SNAP-25 KI mice (see Table 1) This likely

represents an example of ldquodematurationrdquo in which matureneurons are reversed to a pseudoimmature status In thestudy by Kobayashi et al the dose of FLX used to treatwild-type mice was higher than the doses used in otherstudies using both wild-type mice [25 26] and mouse modelof depression [27 28] This FLX-induced iDG caused byldquodematurationrdquo may be related to the antidepressant-inducedmaniapsychosis observed in clinical settings

Recently a second group reported that FLX treatmentinduced an immature state in basolateral amygdala neuronsin adult brains [36] In their study chronic FLX treatmentreduced the percentage of neurons containing perineuronalnets (PNNs) and expressing parvalbumin (PV) in the regionPNNs predominantly surround mature PV-positive fast-spiking (FS) neurons PNNs develop late in postnatal devel-opment and their formation coincides with the closure ofcritical developmental periods and the maturation of PV-positive neurons [37 38] During the critical period absenceof PNNs is thought to allow the induction of synaptic plastic-ity Degradation of PNNs could reactivate synaptic plasticityin adult brain [39 40] Thus FLX treatment shifted the PV-and PNN-containing neurons toward an immature state inthe adult basolateral amygdala [36] The amygdala plays acrucial role in fear-related behaviors Chronic FLX treatmenthas been thought to increase synaptic plasticity convertingfearmemory circuitry to amore immature state subsequentlyallowing erasure of that fear memory A bidirectional regula-tion of neuronal maturation in both the DG and amygdalacould be an important mechanism of FLX action In termsof regulation of neuronal maturation chronic FLX treatmenthas also been shown to reactivate ocular dominance plasticityin the adult visual cortex [41] Considering that oculardominance plasticity is restricted to a critical period duringpostnatal development [39] chronic FLX treatment couldreinstate a juvenile-like form of that plasticity in adulthoodThese findings suggest that ldquodematurationrdquo of neurons causedby FLX is not specific to the DG granule cells

In addition to FLX another SSRI paroxetine is mostlikely to induce ldquodematurationrdquo of DG granule cells inadult mice Chronic paroxetine treatment has been foundto suppress calbindin and Dsp expression in the DG [531] and reduce frequency facilitation at mossy fiber-CA3synapses (mossy fiber synapses formed by immature granulecells exhibit smaller frequency facilitation) [5] These resultssuggest that serotonergic antidepressants can reverse the stateof neuronal maturation in the adult DG

Individuals with epilepsy are at significant risk of psy-chosis with emerging behavioral features that include hal-lucinations mood instability mixed irritability and maniaRecent genetic studies have shown that chromosome copynumber variations such as the 15q133 microdeletion asconferring an increased risk for developing psychosis andepilepsy and suggest that common phenotypes in epilepsyand psychosis may share a genetic basis

Pilocarpine-induced seizure is a well-established rodentmodel of temporal lobe epilepsy Based on previous evidencedemonstrating a permanent reduction in calbindin mRNAand protein expression from the hippocampus of rats fol-lowing pilocarpine treatment (and a similar reduction in

8 Neural Plasticity

0

1

2

3Re

lativ

e exp

ress

ion

120572-CaMKII HKO mice

Control120572-CaMKII HKO

lowastlowast

lowastlowast lowastlowast

120573-Actin Drd1a Dsp Tdo2

(a)

0

05

1

15

2Shn-2 KO mice

Rela

tive e

xpre

ssio

nShn-2 KO


Control


(b)

0

2

4

6

8

Fluoxetine-treated mice

Rela

tive e

xpre

ssio

n

FLX

lowastlowast


Control


(c)

0

1

2

3

4

5

6

Pilocarpine-treated mice

Rela

tive e

xpre

ssio

n

lowastlowast


PilocarpineControl


(d)

Figure 5 Identification of the iDG phenotype using real-time polymerase chain reaction iDG is characterized by upregulation of dopaminereceptor D1a (Drd1a) and downregulation of both desmoplakin (Dsp) and tryptophan 23-dioxygenase (Tdo2) in the hippocampus Asterisksindicate statistical significance determined using the Studentrsquos 119905-test (lowastlowast119875 lt 001 119899 = 4ndash7 per group) Adapted from Yamasaki et al [1] Takaoet al [2] Kobayashi et al [5] and Shin et al [6]

human epileptic brains post mortem) it was hypothesizedthat mice with pilocarpine-induced seizures also exhibit aniDG phenotype Establishment of the iDG phenotype in thismouse model of epilepsy was expected to further support thelink between the pathophysiologies of epilepsy and psychosisMolecular markers for the iDG phenotype were demon-strated in mice with pilocarpine-induced seizures including

dysregulated geneprotein expression of calretinincalbindinas well as hallmark alterations in other iDG markers suchas Drd1a Tdo2 and Dsp Mice with pilocarpine-inducedseizures also displayed characteristic iDG phenotypes atthe electrophysiological levels including decreased polariza-tion of resting membrane potentials lower spike thresholdcurrents in their DG granule cells [6] Although these

Neural Plasticity 9

Table 1 Behavioral electrophysiological and molecular phenotypes in mice with iDG

120572-CaMKIIHKO [1]

Shn-2 KO[2]

SNAP-25KI [3]

CN KO[4 10 21]

FLXtreatment [5]

Pilocarpinetreatment [6]

Behavioralphenotypes

Locomotor activity uarr uarr uarr uarr uarrdarr [29] uarr

Working memory darr [1ndash12] darr darr darr darr [6 30]

Social interaction Mutants killcagemates darr darr darr darr

PPI mdash darr darr darr mdash

Electrophysiologicalphenotypes

Mossy fibre-CA3 synapseBasal transmission uarr uarr mdash mdashFrequency facilitation darr darr darr darr mdashGranule cell somaPassive

Input resistance uarr uarr mdash mdash mdashActive

Excitability uarr uarr uarr uarr uarr

Spike number darr darr uarr uarr uarr

Molecularphenotypes

Markers of immature granule cellsDopamine D1 receptor (Drd1a) uarr mdash uarr uarr uarr [31] uarr

Calretinin uarr uarr uarr uarr uarr uarr

Markers of mature granule cellsTryptophan 23-dioxygenase(Tdo2) darr darr darr darr darr darr

Desmoplakin (Dsp) darr darr darr darr darr darr

Calbindin darr darr darr darr darr darr

GluR1 darr [32] darr darr mdashImmediate early genes inductionc-Fos or Arc-dVenus darr [1 13] darr darr darr darr

Inflammation-related moleculesGlial fibrillary acidic protein(GFAP) mdash uarr uarr uarr uarr [31] uarr [33]

Complement components mdash uarr uarr uarr [31] uarr [34]MHC genes mdash uarr uarr uarr [31] uarr [34]Adult neurogenesisBrdU incorporation uarr darr uarr uarr [25] uarr [33 35]

uarr Increased or upregulateddarr Decreased or downregulatedmdash Nonsignificant

characteristics resemble those found in 120572-CaMKII HKODG granule cells in pilocarpine-treated mice exhibited asignificant increase in repetitive spiking by sustained depo-larizing currentsThis was in sharp contrast to the 120572-CaMKIIHKO which showed relatively few spikes following thesame stimulation protocol Granule cells from pilocarpine-treated mice resemble neurons observed in chronic FLX-treated mice Therefore similar to what was observed asa result of pilocarpine treatment in mice seizure-inducedchanges in the epileptic brain may lead to a ldquodematurationrdquoof DG granule cells resulting in an iDG [6] Remarkablythe behavioral phenotypes of mice with pilocarpine-inducedseizures are similar to those found in earlier iDG mouse

models specifically hyperlocomotor activity working mem-ory deficits and social withdrawal

5 iDG Phenotype and HumanPsychiatric Disorders

The discovery of an iDG phenotype in multiple strains ofmice with behavioral abnormalities suggests a link betweeniDG and the distinct behavioral traits characteristic ofschizophrenia and other psychiatric disorders To assesswhether iDG is related to human psychiatric disorders com-prehensive gene expression data from 166 hippocampi wereanalyzed from human brains postmortem including brains

10 Neural Plasticity

of 21 patients with psychiatric disorders Comprehensive geneexpression analysis was performed using a specific biomarkerset derived from 120572-CaMKII HKO mice including 10 genesselected (ADCY8 CCND1 LOC151835 LOC284018 NTNG1PDYN PIP3-E PNCK SPATA13 and TDO2) due to differ-ential expression in the iDGmutant hippocampus Statisticalclustering of the gene expression datawas performed using all166 hippocampi from human brains collected postmortemThe analysis roughly classified subjects into 2 clusters one ofwhich (schizophrenia-enriched cluster) contained 19 of the 21patients with psychiatric disorders (including schizophreniaschizoaffective and bipolar patients) [1] Furthermore thegene expression profile was compared between the patientswith schizophrenia in the schizophrenia-enriched cluster andthe individuals with no major psychiatric diagnosis and 26differentially expressed probes were identified in the patientswith schizophrenia Interestingly 12 of the 26 identified geneswere related to neurogenesis and cell-maturationmigrationthese 12 included calbindin whose expression was reducedby gt60 in the schizophrenia-enriched cluster In a similarindependent study Altar et al conducted DG transcriptomeanalysis in human patients with schizophrenia [43] andindicated that calbindin was significantly downregulated inthe DG of these patients

Patients with schizophrenia and those with bipolar disor-der have also been examined for themolecular characteristicsof the iDG phenotype Postmortem immunohistochemicalanalysis of brain tissue revealed that patientswith schizophre-nia and those with bipolar disorder display significantlyelevated calretinin expression in the DG compared to bothcontrol subjects and patients having major depression Theincrease of calretinin is strongly correlated with a history ofpsychosis Moreover compared to both control subjects andpatients having major depression patients with schizophre-nia and thosewith bipolar disorder have significantly elevatedratio of calretinin to calbindin [7] These facts demonstratethat an iDG-like condition may be also found in humanpatients with schizophrenia andor bipolar disorder

A mouse model of schizophrenia that expresses theiDG phenotype (Shn-2 KO mice) has been shown to dis-play a series of brain phenotypes found in schizophreniaThese phenotypes include decreased gamma-aminobutyricacidergic (GABAergic) neuronal molecules (ie PV glu-tamic acid decarboxylase isoform 67 (GAD67) Gabra1 etc)reduction of oligodendrocyte markers (myelin basic proteinand 2101584031015840-cyclic-nucleotide 31015840-phosphodiesterase (CNPase))thinner cortex and abnormal electroencephalographic find-ings (increased theta waves and decreased gamma waves)The gene expression pattern in Shn-2 KOmice was comparedwith that in patients with mental disorders obtained frompublicly available array data using the bioinformatics toolNextBio (Cupertino CA USA) NextBio is a repository ofanalyzed microarray datasets that allows an investigator tosearch results and the expression profiles of publicly availablemicroarray datasetsThis analysis determined that the highestdegree of gene expression overlap was detected from Broad-mann area 10 (BA10) in postmortem tissue from patientswith schizophrenia and from control subjects with 100 genescommonly altered in both Shn-2 KO mice and patients with

schizophrenia [2] The similarity was extraordinal (119875 =95 times 10

minus14) which is unlikely to be obtained by chanceFurthermore the expression levels of 76 of these 100 geneswere altered in the same directions (Figures 6(a) and 6(b))These findings support the idea that iDG or an equivalentphenomenon could also be present in human brain

6 Maturation Abnormalities of Neurons otherthan DG Granule Cells in Humans withPsychiatric Disorders

Growing evidence from postmortem research implicatesabnormal neurodevelopment in the pathogenesis of schiz-ophrenia and other psychiatric disorders In addition todetection of the iDG-like conditionmentioned earlier imma-turity of neurons other than DG granule cells has also beenshown in the brains of patients with psychiatric disorders

The maturation of GABA signaling is characterized byprogressive switches in expression from GAD25 to GAD67and from NKCC1 to KCC2 in the prefrontal cortex (PFC)and hippocampus of human brain GAD25 is predominantlyexpressed in the fetus whereas GAD67 is stably expressedacross development [44] GABA synthesis is increased con-currently with the switch fromGAD25 toGAD67The cation-chloride cotransporters NKCC1 and KCC2 contribute tochange of GABA from an excitatory to an inhibitory neuro-transmitter in developing brain NKCC1 expression predomi-nates early in the developmental period andKCC2 expressionrises as brain development progresses [44 45] In the hip-pocampus of patients with schizophrenia GAD25GAD67and NKCC1KCC2 ratios are increased and KCC2 expressionis significantly decreased indicating a potentially immaturestate in a certain type of GABAergic neurons [44]

Decreased levels of PV have been shown in brains ofindividuals with schizophrenia [46ndash49] and bipolar disorder[50] Because PV is known to be a marker of mature FSinhibitory neurons FS cells were hypothesized to be imma-ture in these psychiatric disorders [51 52] In this contextGandal et al developed an FS cell maturation index Usingtime-course gene expression data from developing FS cellsthat were positively correlated with PV expression levelsthey showed a reduction of the index in cortices of patientswith schizophrenia bipolar disorder and autism [52] Theseresults suggest that FS neurons are arrested in an immature-like state in the cortices of patients with these psychiatricdisorders

Furthermore reduction of PNNs has been reported inthe lateral nucleus of the amygdala and in layer II of thelateral entorhinal cortex of subjects with schizophrenia [3853] PNNs are chondroitin sulfate proteoglycan-(CSPG-)containing neural extracellular matrices and are particularlyenriched around PV-positive inhibitory neurons Becausenumbers of PV-positive cells are normal within these regionsin schizophrenia the reduction of PNNs indicate downreg-ulated CSPG levels rather than loss of PNN-associated neu-rons [53 54] Disruption of PNN formation is thought to leadmaturation abnormalities in selective neuronal populationsincluding those expressing PV [39 40] Since PNNs develop

Neural Plasticity 11

LPS

treat

men

t (fo

ld ch

ange

)Pr

ion

infe

ctio

n (fo

ld ch

ange

)

Agi

ng (f

old

chan

ge)

Inju

ry (f

old

chan

ge)

Shn-2 KO mice(fold change)




01

1

10

0 1 2 301

1

10

100

0 1 2 3

01

1

10

100

0 1 2 30

1

2

3

4

0 1 2 3 4

(a)

(b)(f)(e)

(d)(c)

0

1

2

3

0 1 2

34 genes

42 genes 16 genes

8 genes

Schi

zoph

reni

a (fo

ld ch

ange

)


lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

Gene nameShn-2 KO Schizophrenia

Fold change

154 285137 238139 220125 201minus125 minus196131 182131 178122 minus170minus144 minus168

140 167minus230 minus165153 162120 161minus230 minus159125 158

158153CbIn4Tgm2Ma12

Sic14a1Mthfd2

GfapRgs4

D0H4S114Fbxo9Syn2

Gadd45bGabralChmICebpbCar10Rab3bTasp1Hk2

RP11ndash35N61Gng4

Ms4a6bKlf10Fcgr3Nrxn3

minus181138minus135134minus129170minus125minus124minus123147165minus132122139127minus125minus124125minus120minus226131165127minus122

minus156156minus152152150148minus148minus147minus146minus145144minus143minus143141minus141minus141minus140139minus138minus137137minus136135minus135

Serpina3nC1qbC1qc

C10orf10Rgs4

Ifitm2C1qaMyt1lTac1

CebpdFrzb

Ifitm1

Ifitm1

Tgfbr1Frzb

Ddit4

Figure 6 Comparison of gene expression profiles between Shn-2 KO mice and individuals with schizophrenia (a) Scatter plot of geneexpression fold change values in the medial prefrontal cortex (mPFC) of Shn-2 KO mice and Brodmann area (BA) 10 of postmortemschizophrenia brain (b) Genes differentially expressed in both Shn-2 KO mice and in schizophrenia Red indicates gene upregulation andblue indicates downregulation in both Shn-2 KO mice and in schizophrenia The top 40 genes with respect to the fold change values areincluded Asterisks indicate inflammation-related genes (c)ndash(f) The hippocampal transcriptome pattern of Shn-2 KO mice was similar tothe transcriptome data from lipopolysaccharide (LPS) treatment ((c) 119875 = 56 times 10minus9) injury ((d) 119875 = 57 times 10minus24) prion infection ((e)119875 = 10 times 10

minus18) and aging ((f) 119875 = 14 times 10minus26) Adapted from Takao et al [2]


late in postnatal development and coincide with the mat-uration of PV-positive neurons [38 40] the reduction ofPNNs may imply that the PV-positive neurons remain at animmature-like state in the amygdala and entorhinal cortex ofsubjects with schizophrenia

Taken together these findings suggest that immaturity ofneurons in adult brain can be seen not only in the DG butalso in other brain regions in humans with psychiatric dis-orders Further studies that focus on defining the maturationstate of cells could identify maturation abnormalities of cellsin additional brain regions

7 Potential Mechanisms Underlying iDG

When attempting to fully understand the iDG phenotype alogical next question is what are the underlying mechanismscausing iDG Both genetic and pharmacological manipula-tions have been shown to induce the iDG phenotype andthese factors could provide clues towards identifying themechanisms behind this phenotype

71 Inflammation One clue into these mechanisms may liein the normal functions of genes that when altered producemouse models that express the iDG phenotype For exampleShn-2 can be linked to the inflammatory cascade in thatShn-2 was originally identified as a nuclear factor-kappaB (NF-120581B) site-binding protein that tightly binds to theenhancers ofmajor histocompatibility complex (MHC) genesin the MHC regions of chromosome 6 [55] Recent genome-wide association studies have identified a number of singlenucleotide polymorphisms (SNPs) in theMHCregion associ-atedwith schizophrenia [56ndash60]There are severalMHCclassI genes (HLA-A HLA-B etc) each with similar promoterstructures that have 2 NF-120581B binding motifs [61] Uponinflammation NF-120581B is known to bind to these enhancersand to initiate transcription of genes involved in immunefunctions Shn-2 binds these motifs but does not substitutefor the transcriptional function of NF-120581B [62] Instead Shn-2 competes with NF-120581B for binding to the motifs and inhibitsNF-120581B activity It has been reported that Shn-2 KOmice haveconstitutive NF-120581B activation and that T-cells of these miceshow dramatic enhancement in differentiation towards T-helper Type 2 cells (Th2) a phenomenon called ldquoTh2 slantrdquo[63] which is observed in patients with schizophrenia [64]Thus Shn-2 is an inhibitor of NF-120581B a major mediator ofinflammation

Due to the link between Shn-2 and inflammation alteredgene expression patterns were expected in Shn-2 KO miceUsing the bioinformatics tool NextBio publicly availabledatasets were analyzed to find the conditions where tran-scriptome patterns are similar to those found in the PFCof Shn-2 KO mice Gene expression patterns in the PFCof Shn-2 KO mice were found to be similar to those seenin inherently inflammatory conditions (eg prion infectionmalaria encephalopathy spinal cord injury brain injury andkidney tissue treated with lipopolysaccharide) (Figures 6(c)ndash6(f)) However this analysis highlighted that the scale ofinflammation for Shn-2 KO mice is quite different fromother inflammatory conditions (ie the inflammation in

Shn-2 KO mice is much weaker in terms of the magnitudeof the changes) Additionally it was found that many ofthe genes with altered expression in both Shn-2 KO miceand patients with schizophrenia were inflammation-relatedgenes (Figure 6(b)) Astrocytic activation is considered anindication of inflammation and GFAP a reactive astrocytemarker is increased not only in Shn-2 KO mice but also inSNAP-25 KI [3] FLX-treated [65] and pilocarpine-treatedmice [33] Therefore the iDG phenotype can be associatedwith inflammation-like phenomena

72 Neuronal Hyperexcitation In pilocarpine-inducedepilepsy mouse models a single episode of status epilepticus(SE) was not enough to induce the iDG phenotype Chronicmodels of animal epilepsy develop spontaneous recurrentseizures (SRS) following SE over a period of months or yearsIn mice with pilocarpine-induced epilepsy the markers ofthe iDG phenotype were identified in mice that developedSRS following SE but not in mice that after pilocarpine-induced SE did not develop SRS [6] These findings have 2potential interpretations (1) tonicchronic hyperexcitationof hippocampal neurocircuits leading to SRS is neededto induce the iDG phenotype or (2) the iDG phenotypeitself is necessary for the development of SRS However arepresentative model of iDG (120572-CaMKII HKO mice) has amore than 4-fold increase in sensitivity to pilocarpine fortriggering seizures but not developing SRS

Recently it has been reported that SNAP-25 KI micesometimes exhibit spontaneously occurring convulsiveseizures after postnatal days 21ndash24 [66] These seizures canbe suppressed with chronic administration of valproic acidan anticonvulsant starting at postnatal day 16 [67] Thesefindings led to an investigation of whether iDG phenotypesand behavioral abnormalities could be rescued in mutantmice by suppression of recurrent epileptic seizures withvalproic acid Results showed that in the DG of SNAP-25KI mice decreased expression of calbindin and increasedexpression of calretinin could be rescued with chronicadministration of valproic acid Valproic acid treatmentalso reduced the previously observed increase in the sizeof the DG and significantly improved working memory inthese mice [3] These results suggest that recurrent epilepticseizures underlie ldquodematurationrdquo of DG granule cells whichinduce the iDG phenotype

Hyperexcitability of the DG granule cells is a featureshared among mice that express the iDG phenotype Thethreshold current required to induce an action potential isreduced in 120572-CaMKII HKO Shn-2 KO SNAP-25 KI andFLX-treated mice (Table 1) Furthermore the increased sen-sitivity to pilocarpine (with respect to the seizure threshold)in 120572-CaMKII HKO mice supports the idea that hyperexci-tation induces the iDG phenotype [6] Previous studies havereported region-specific loss of GABAergic inhibition follow-ing SESRS especially from theCA1CA3 andhilar regions inthe hippocampus Notable molecularmorphological deficitsobserved in iDG mouse models include a reduction of theGABAergic system in the hippocampus (eg a reduction ofPV-positive interneurons and decrease of GAD67 expressionTakao et al [2]) Although it is probably too simplistic


to conclude (or even to speculate) that a simple loss ofGABAergic cells andor function from the hippocampusmaycontribute to induction of the iDGphenotype these data sug-gest that sustained hippocampal neuronal hyperexcitationcaused by loss of GABAergic inhibition may be a commondriving force for initiating a cascade of molecular events thatlead to development of the iDGphenotype Collectively thesefindings support the idea that neuronal hyperexcitation leadsto ldquodematurationrdquo of mature granule cells in the DG therebycontributing to iDG phenotypes

It should also be noted that iDG phenotypes are usuallyassociatedwithmild chronic inflammation Shn2-KO SNAP-25 KI pilocarpine-treated FLX-treated and paroxetine-treated mice commonly demonstrate upregulated expressionof complement and MHC genes and GFAP suggesting thatneuronal hyperexcitation is a source of inflammatory-likeprocesses in the brains of these mice In contrast recentresearch has highlighted the involvement of the immunesystem in the development of epilepsy For instance inflam-matory cytokines are increased in the central nervous sys-tem (CNS) and plasma of epilepsy model animals and ofpatients with epilepsy [68 69] Moreover inflammation inthe CNS is associated with damage to the blood-brain barrier(potentially leading to leakage) that is known to enhanceneuronal excitability and has been implicated in epileptogen-esis [70ndash72] In this context Fabene et al demonstrated thatpilocarpine-induced SE enhances leukocytic inflammatorychanges in the CNS vasculature consequently generatingepileptic activity [73] Based on these data a possible positivefeedback mechanism between neuronal hyperexcitation andinflammatory conditions could subsequently induce iDGphenotypes

More recently it has been reported that knockdown ofDisc1 (disrupted in schizophrenia 1) specifically in adult-born DG neurons results in enhanced excitability [74] TheDisc1 gene was originally discovered in a Scottish familywith a high incidence of psychiatric disorders includingschizophrenia and bipolar disorder [75] Disc1 knockdownalso caused pronounced cognitive and affective deficitswhich could be reversed when affected DG neurons wereinactivated [74] These findings are consistent with thehypothesis that hyperexcitation of DG neurons may underliebehavioral abnormalities related to schizophrenia and otherneuropsychiatric disorders

73 Other Clues The iDG phenotype is associated with sev-eral other cellularmolecular alterations and these changesmay serve as clues to the mechanisms underlying the phe-notype The GluR1 subunit of 120572-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptor is dra-matically reduced in most but not all mice that expressthe iDG phenotype For example it has been reported thatGluR1 expression is reduced in the DG of 120572-CaMKII HKO[32] and Shn-2 KO [2] Interestingly GluR1 is expressedprimarily in mature granule cells and can be used as a markerfor maturation of granule cells [32] Physiologically Ca2+-permeability mediated by GluR1 andor GluR3 subunits isstrongly associated with granule cell maturation [76ndash78]The GluR1 reduction demonstrated in these mutants may be

consistent with the idea that DG granule cells are immaturein these mice

Arc and c-Fos are immediate-early genes (IEGs) thatare commonly used as markers for the maturity of in vivoactivity-dependent responsiveness of granule cells whoseexpression can be stimulus-induced in 3- to 5-week-old cells[79 80] As mentioned previously Arc promoter activitywas dramatically reduced in the DG of 120572-CaMKII miceafter performing working memory tasks [13] Likewise Arcinduction after exposure to a novel environment or receivingelectrical foot shocks was reduced in the DG of Shn-2 KO [2]and SNAP-25 KI mice [3] In FLX-treated mice expressionof c-Fos was reduced after receiving foot shocks [5] Sinceactivity-dependent processes have been implicated in thematuration of adult neural progenitors if reduction of IEGexpression (or conversely promotion of expression) repre-sents a state of low-responsiveness to behavioral stimulationsin the granule cells of mice expressing the iDG phenotypeactivity-dependent maturational mechanisms are also likelyimpaired in these cells However granule cells are moreexcitable in 120572-CaMKII HKO [1] Shn-2 KO [2] SNAP-25KI [3] and FLX-treated mice [5] Therefore suppressed IEGinduction inmice expressing the iDGphenotypemight be theresult of decreased activity andor impairments in activity-dependent gene regulation in the DG

Adult neurogenesis in the DG was assessed usingincorporation of 5-bromo-21015840-deoxyuridine (BrdU) and waselevated in 120572-CaMKII HKO [1] FLX-treated [25] andpilocarpine-treated mice In the pilocarpine model ofepilepsy BrdU incorporation was increased in the acutephase after SE [33] as well as in the period of SRS [35]However despite the occurrence of epileptic seizures inSNAP-25 KI mice reduced adult neurogenesis was observedin thesemutants [3] Further studies are needed to fully assesswhether altered adult neurogenesis is involved in formationof the iDG phenotype Electrophysiologically an increasein granule cell excitability and a reduction of frequencyfacilitation at mossy fibre-CA3 synapses were found in 120572-CaMKII HKO Shn-2 KO SNAP-25 KI and FLX-treatedmice These shared molecular and physiological alternationsinmice with the iDGphenotypemay provide important cluesto investigate the mechanisms underlying iDG

Table 1 summarizes the behavioral electrophysiologicaland molecular patterns in different mice with the iDGphenotype Some endophenotypes are perfectly shared butothers are not There appear to be subgroups of the iDGphenotype which may potentially correspond to differenttypes of psychiatric disorders Furthermore there are likelysome shared and some unshared mechanisms between thedifferent groups of mice with the iDG phenotype

8 Face and Construct Validity of iDG MouseModels as Models of Psychiatric Disorders

Mice with the iDG phenotype possess face validity as animalmodels of schizophrenia at both the behavioral andmolecularlevels In addition various phenomena accompanied by theiDGphenotype are in good agreementwithmost of themajor


hypotheses of the disorder supporting the construct validityof these models

81 Face Validity Asmentioned earliermutantmicewith theiDG phenotype (CN KO 120572-CaMKII HKO Shn-2 KO andSNAP-25KImice) have been identified as potentialmodels ofschizophrenia and bipolar disorder originally by behavioralscreening designed to assess the face validity of this modelThese mutant mice strains commonly exhibited severe work-ing memory deficits decreased PPI impaired social behav-iors and hyperactivity Impairments in working memory[81 82] PPI [83] and social withdrawal [84] are prominentfeatures of schizophrenia symptomatology Hyperactivity ischaracteristic of rodent models of schizophrenia [85] andcould correspond to the psychomotor agitation often presentin patients with schizophrenia Furthermore FLX-treatedand pilocarpine-treated mice express iDG and behavioralphenotypes shown by mutant iDG mice (Table 1) Thereforewhen evaluated at a behavioral level mice expressing theiDG phenotype display a strikingly conserved behavioralphenotype

Among these models Shn-2 KO mice showed outstand-ing face validity as an animal model of schizophreniaIn addition with respect to molecular profiles Shn-2 KOmice shared altered molecular expression patterns withpostmortem brain tissue from patients with schizophreniaSignificant similarities in expression direction andmagnitudewere detected when the gene expression pattern in Shn-2KO medial PFC (mPFC) was compared with the patternin schizophrenic frontal cortex (Brodmann area 10 BA10)examined postmortem [86] 100 altered genes were detectedin both Shn-2 KO mice and patients with schizophrenia Ofthe 100 altered genes 76 showed the same directional changein expression and of the 76 genes 42 were downregulatedand 34 were upregulated [2] A large number of genespreviously implicated in schizophrenia or bipolar disorderwere included in these groups For example 89 of the 100similarly expressed genes have been identified as related tothese disorders Shn-2 KO mice also displayed decreasedlevels of PV in the frontal cortex which has been widelyobserved in schizophrenia [46ndash49] Fast-spiking PV-positiveinterneurons have been shown to be immature in the corticesof patients with schizophrenia bipolar disorder and autism[52] This suggests that immaturity of this type of neuron inthe cortex may underlie some of the cognitive deficits seenin these disorders Shn-2 KO mice also exhibit decreasedexpression of PV and GAD67 in the hippocampus which hasbeen observed in the brains of patients with schizophreniaexamined postmortem [87ndash89] Furthermore Shn-2 KOmice had significantly thinner cortex and reduced cell densityin the prelimbic and primary visual cortices consistent withobservations in human patients with schizophrenia [90]

In addition to anatomical abnormalities the cortex ofShn-2 KO mice exhibits physiological alternations CorticalEEG analysis in mutant mice showed an increase in slowwaves and a decrease in fastwaves both ofwhich are observedin patients with schizophrenia [91ndash93] Although presentstudies have evaluated the molecular and physiological valid-ity using Shn-2 KO mice in detail future studies are needed

to address whether other mouse strains that express the iDGphenotype similarly fulfill the criteria for face validity

82 HyperdopaminergicHypoglutamatergic Hypotheses Thelongstanding ldquodopamine hypothesis of schizophreniardquo isbased primarily on 2 facts (1) all antipsychotics currentlyavailable to treat the positive symptoms of schizophreniapossess dopamine D2 receptor blocking activity and (2)hyperactive dopamine release in subcortical limbic brainregions especially in the nucleus accumbensstriatum hasbeen consistently observed in patients with schizophrenia[94 95] Dopamine D2 blockers are widely used for treatingbipolar mania and hyperactivity of the dopaminergic sys-tem during manic phases has also been proposed [96] Ahyperdopaminergic state in subcortical regions is believed tobe associated with psychosis a core constituent of positivesymptoms of schizophrenia and a phenotype often observedin manic phase of the bipolar disorder and a symptom thatcan be ameliorated using treatment with D2 blockers

Intriguingly 120572-CaMKII HKO mice have been proposedas amodel of schizophrenia byNovak and Seeman [97] basedon their finding that D2High receptors were elevated in thestriatum (representing hyperdopaminergic state analogousto schizophrenia) of this mutant strain Increasing evidencealso supports that mice with iDG phenotypes are in ahyperdopaminergic state For example administration ofhaloperidol a typical antipsychotic significantly improvedPPI impairment in Shn-2 KO mice [2] Currently availableantipsychotics (including haloperidol) work primarily byantagonizing dopamineD2 receptors and raising intracellularcAMP levels Therefore intracellular stimulation of cAMPlevels is thought to have effects similar to treatment withantipsychotic medication [98 99] Rolipram is a cAMP-specific phosphodiesterase inhibitor that elevates intracellu-lar cAMP levels Chronic treatment with rolipram (in combi-nation with ibuprofen) rescued a subset of mice expressingthe iDG phenotype and improved working memory andnest building in Shn-2 KO mice These findings suggest thatlower intracellular cAMP levels are involved in a subset ofbehavioral abnormalities and iDG phenotypes

Interestingly dopamine D1 signaling is also upregulatedin the DG of 120572-CaMKII HKO and Shn-2 KO mice whenassessed using receptor binding assay and receptor agonistsensitivity respectively Increased expression ofDrd1amRNAalso suggests elevated D1 signaling in 120572-CaMKII [1] SNAP-25 KI [3] FLX-treated [65] and pilocarpine-treated mice[6] Upregulated D1 signaling might serve as a compensatorymechanism to normalize intracellular cAMP levels in thesemice These results suggest the presence of a hyperdopamin-ergic state in the brains of mice with the iDG phenotype

This hyperdopaminergic state is thought to be a con-sequence of NMDA receptor hypofunction This assertionis supported by findings showing that acute applicationof an NMDA receptor antagonist stimulates dopaminerelease in both animal models and humans CaMKIIis a major downstream molecule of the NMDA recep-tor and plays an important role in long-term potenti-ation and long-term depression [100] Since deficiencyof 120572-CaMKII causes schizophrenia-related behavioral and


iDG phenotypes NMDA receptor hypofunction might beinvolved in the formation of the iDG phenotype In additionin 120572-CaMKII HKO mice NMDA receptor- binding was alsodownregulated in the hippocampus especially in the DG[1] supporting the idea of NMDA receptor hypofunction inthese mutant mice Additional evidence for this hypothesisincludes the fact that MK-801 an NMDA receptor antag-onist that causes schizophrenia-like psychosis in humansproduced significantly higher levels of drug-stimulatedmotor activation in CN KO [10] and Shn-2 KO mice [2]Taken together these findings suggest that hypoglutamater-gichyperdopaminergic function is involved in the iDGphenotype

83 NeurodevelopmentalNeurogenesis Hypothesis The neu-rodevelopmental hypothesis is one of the major theoriesregarding the pathogenesis of schizophrenia [101ndash103] Thishypothesis is supported by several lines of evidence includingincreased frequency of obstetric complications in patientswith schizophrenia the presence of neurological cognitiveand behavioral dysfunction long before illness onset theabsence of postmortem evidence of neurodegeneration andthe induction of schizophrenia-like phenomena by neonatalhippocampal lesions in model animals [101 103ndash105] Thesefindings are consistent with a neurodevelopmental model inwhich the etiology of schizophrenia may involve pathologicprocesses caused by both genetic and environmental factorsthat begin before adolescence when the brain approaches itsadult anatomical state

The iDG phenotype literally reflects a neurodevelopmen-tal problem in which DG granule cells arrest in a pseu-doimmature state Takao et al revealed that iDG phenotypesemerge at 2ndash4 weeks of age in Shn-2 KO mice [2] In 2-week-old mice there were no significant differences in theexpression of calbindin and calretinin in the DG of Shn-2KO and wild-type mice However when mice were evaluatedat 1 month of age calbindin expression was decreased andcalretinin was increased in the DG of Shn-2 KO miceindicating the postnatal (possibly adolescent) emergence ofan iDG phenotype

Specifically the number of calbindin-positive cells wasdecreased at age of 4 weeks compared to age of 2 weeksin Shn-2 KO mice whereas in wild-type mice thesecells increased throughout development Even in adultwild-type mice ldquodematurationrdquo of mature granule cellsand schizophrenia-related behavioral phenotypes could beinduced by chronic FLX treatment [5] or with pilocarpine-induced SRS [6] These findings suggest that genetic andorenvironmental factors could induce the maturational abnor-malities of DG granule cells during the postnatal develop-mental period (and during adulthood)

Elevated neurogenesis has been defined as a core featureof the pathology associatedwith the iDGphenotype with fewexceptions (see [3]) One study supports a linkage betweenschizophrenia and decreased hippocampal neurogenesis astissues from human patients with schizophrenia had fewerproliferating Ki-67 cells than tissues from control subjects[112] However that study excluded several patients withneurogenesis levels greater than 5-fold baseline levels which

may represent a subset of patients with schizophreniabipolardisorder that display hyperactive neurogenesis

84 Inflammation Hypothesis The well-established role ofinflammation in the etiology of schizophrenia is oftenreferred to as the inflammation hypothesis [64 113ndash115]The link between prenatal infection and schizophrenia wasfirst identified in an epidemiological study demonstratingincreased schizophrenia risk in the offspring of womenexposed to influenza during pregnancy [64] Several otherinfectious factors have also been implicated in the pathogen-esis of schizophrenia [64] suggesting that the disease mayresult from maternal immune response to infection To thisend prenatal treatment with polyinosinicpolycytidylic acid(poly IC) viral infection and LPS treatment are used asrodent models of schizophrenia [114 116ndash119] As mentionedpreviously Shn-2 KO mice were shown to exhibit mildchronic inflammation of the brain as evidenced by increasedinflammation markers (including complement and MHCclass I genes GFAP and NADHNADPH oxidase p22-phox)and genome-wide gene expression patterns similar to variousinflammatory conditions [2] Similarly SNAP-25 KI micewhich develop epileptic seizures showed increased expres-sion of complement and MHC class I genes and GFAP inthe hippocampus [3] In FLX-treated [65] paroxetine-treated[31] and pilocarpine-treated animals [34] gene chip datareveals hippocampal upregulation of complement and MHCgenes and GFAP Therefore the changes in inflammation-related molecules in these mice with iDG are consistent withinflammatory features found in the brains of patients withschizophrenia and epilepsy

85 Collection of Genetic Association Study ResultsSchizophrenia is highly heritable and multiple geneticand environmental factors are probably be involved [120]Mice with iDG phenotype exhibit significantly alteredexpression of genes that have been reported to associate withschizophrenia

For example mutated genes that cause iDG phenotypehave been implicated in schizophrenia by association studiesBased on the observation that CN KO mice display aspectrum of behavioral abnormalities strikingly similar tothose observed in patients with schizophrenia [21] Gerberet al examined whether CN dysfunction is involved in theetiology of schizophrenia [9] By conducting transmissiondisequilibrium studies in a large sample of affected familiesthey reported evidence supporting an association betweenthe PPP3CC gene encoding the CNA-gamma catalytic sub-unit and schizophrenia in populations from the United Statesand South Africa The allelic and haplotypic associationsof PPP3CC with schizophrenia were later confirmed inpopulations from Japan [20] Thus CN KO mice have goodconstruct and face validity as a model for schizophrenia

Moreover recent genome-wide association studies haveidentified a number of SNPs in the MHC region associatedwith schizophrenia [56ndash59] Many of these SNPs are locatedin or near NF-120581B binding sites that may be associatedwith susceptibility to schizophrenia [2] Some of the genessurrounding these SNPs are dysregulated in the brains of


patients with schizophrenia examined postmortem andorthe PFC of Shn-2 KO mice As Shn-2 is a MHC enhancer-binding protein that binds to the NF-120581B binding motifabnormal transcription of these genes may be induced bydysregulated NF-120581B signaling pathways independent of anydeficiency or mutation in Shn-2 itself

In addition recent human genetic studies have discov-ered associations between SNAP-25 and various psychiatricand neurological disorders including schizophrenia [14 15]ADHD[16 17] and epilepsy [18 19] Translational convergentfunctional genomic study demonstrates that SNAP-25 isone of the top 42 candidate genes for schizophrenia [121]Therefore SNAP-25 KI mice also have strong constructvalidity for schizophrenia

Many of the genes with decreased expression in bothschizophrenic BA10 and Shn-2 KOmPFC have been reportedto be associated with schizophrenia Chowdari et al reportedthat several SNPs inRGS4 regulator ofG-protein signaling-4are associatedwith schizophrenia [122] It has been previouslyshown that RGS4 expression is decreased across 3 corticalareas (including the PFC) of subjects with schizophrenia[123] Consistent with these observations RGS4 mRNAexpression was decreased in the mPFC of Shn-2 KOmice [2]Additionally significant associations were detected betweensamples from patients with schizophrenia and SNPs in Cbln4[57] Gabra1 [124] and Nrxn3 [57] These genes are involvedin synaptic transmission or synaptic plasticity and expressionof these genes is commonly decreased in both schizophrenicBA10 and Shn-2 KO mPFC Thus decreased expression ofgenes associated with schizophrenia could play a significantrole in developing schizophrenic conditions in the PFC ofiDG mice especially of Shn-2 KO mice

Genes related to neuronal excitation and inflamma-tory responses have been reported to be associated withschizophrenia [125] As previously mentioned these condi-tions are closely related to induction of the iDG phenotype Ameta-analysis of clinical data showed an association betweenSNPs in KCNH2 (a human Ether-a-go-go-family potassiumchannel) and schizophrenia [126] The KCNH2-31 isoformmodulates neuronal firing and its expression is increased inthe hippocampi from individuals with schizophrenia sug-gesting increased neuronal excitability in the schizophrenicbrain [126]

Regarding inflammatory or immune response-relatedgenes as previously mentioned a number of SNPs in theMHC region are associated with schizophrenia In additionmany inflammatory response-related genes such as C1QAC1QB [127] TAC1 [128 129] TGFBR1 [129] and TGM2 [130]have been associatedwith schizophreniaGFAP is also knownto have a significant association with schizophrenia [15]These mRNA expression changes were in the same directionas changes seen in schizophrenic BA10 and Shn-2 KO mPFC[2] Thus it has been established that altered expressionof genes related to neuronal excitation and inflammatoryconditions could be involved in the brains of patients withschizophrenia as well as in mice with iDG phenotype

Taken together these findings indicate that mice withthe iDG phenotype have high construct validity as animal

models of schizophrenia with many of the genes showing asignificant association with schizophrenia

86 Other Factors Some other factors such as dysfunction ofoligodendrocytes or mitochondria have been implicated inpsychiatric disorders Several potential deficits were observedin key oligodendrocyte markers including decreases inCNPase and myelin basic protein (MBP) which is a majorconstituent of the myelin sheath of oligodendrocytes andSchwann cells Decreased CNPase protein levels have beenreported in schizophrenia [131] Similarly MBP mRNAlevels were decreased in the DG as well as the mPFCof Shn-2 KO mice and proteome analysis reveled thatmany mitochondria-related proteins (eg dihydrolipoamideS-acetyltransferase (DLAT) ubiquinol-cytochrome 119888 reduc-tase core protein (UQCRC) and NADH dehydrogenase[ubiquinone] Fe-S protein (NDUFS)) in the DG are affectedin Shn-2KOmice [2 132]These findings suggest that changesin the expression of molecules related to oligodendrocytes ormitochondria in the DG of Shn-2 KO mice would be consis-tent with the oligodendrocyte and mitochondria hypothesesof schizophrenia respectively

Figure 7 shows a schematic representation of the modeldetailing how the iDG phenotype may be involved inschizophrenia bipolar disorder and other psychiatric disor-ders This proposed model is based on the findings that micewith the iDGphenotype possess face and construct validity asanimalmodels of these disorders In these disorders multiplegenetic and environmental factors could inducemild chronicinflammation and this could subsequently result in multipleendophenotypes (including iDG) in the brain that may as awhole cause behavioral abnormalities in psychiatric patients

9 A Possible Role of iDG inBehavioral Abnormalities Relevant toNeuropsychiatric Disorders

91 iDG and Working Memory Impairment in workingmemory is one of the core behavioral abnormalities in micewith the iDGphenotype CNKO [21]120572-CaMKIIHKO [1 12]Shn-2KO [2] SNAP-25 KI mice [3] and pilocarpine-treatedanimals [30] have been reported to display severe workingmemory deficits in the spatial workingmemory version of theeight-arm radial maze andor in the T-maze forced-alterationtask

The hippocampal structure has been shown to be criti-cally involved in working memory function [133 134] TheDG is a key input node for the hippocampal structurePerforant path fibers originating in the entorhinal cortexprovide a major source of highly processed sensory infor-mation to DG granule cells When rats with lesions in theDG were tested on working memory version of the eight-arm radial maze they showed impairment in their abilityto perform this version of the task [135ndash137] Consideringthe evidence supporting involvement of the DG in workingmemory function it is likely that the iDG phenotype has anegative impact on working memory function However thepossibility that deficits in regions other than the DG cause


Molecular and cellulardisruption

Neural circuits andsystems dysfunction

Candidate endophenotypesin the brain

Altered neurogenesis

iDG

Mild chronic inflammation

Oligodendrocyte dysfunction

Behavioral abnormalitiessymptoms

Human psychiatric patients

Working memory deficits

Decreased PPI

Psychomotor agitation

Model mice

Hyperlocomotor activity


Decreased PPI

Social withdrawal

Behavioral andcognitive deficits

Causes

Activated astrocytes

Mitochondrial dysfunction

Hyperdopaminergic state

Hypoglutamatergic state

Impaired nest buildingabnormal social behavior

Human psychiatricpatients

Animal models ofpsychiatric disorders

Genetically engineered mice

Life events drugsprenatal infection etc

Pilocarpine-induced seizures

Chronic SSRI

120572-CaMKII HKO Shn-2 KOSNAP-25 KI CN KO

Chronic SSRI

Geneticfactors SNPs CNVs etc

Environmentalfactors

Neuronalhyperexcitation Epilepsy

stress poly I C model

Figure 7 A schematic representation of the model of involvement of the iDG phenotype in psychiatric disorders In psychiatricdisorders such as schizophrenia bipolar disorder and depression multiple genetic and environmental factors could induce mild chronicinflammationThis could subsequently result inmultiple endophenotypes in the brain including iDG Inflammation could induce alterationsin neurogenesis [106 107] mitochondrial dysfunction [108 109] and oligodendrocyte dysfunction [110 111] Involvement of inflammation ininduction of a hypoglutamatergic state or hyperdopaminergic state remains unclear These possible endophenotypes may affect each otherwhich may in turn cause behavioral abnormalities in psychiatric patients There may not be a single ldquoprincipalrdquo or ldquocorerdquo mechanism thatunderlies the behavioral symptom of psychiatric disorders Indeed a shared or preserved set of multiple endophenotypes as a whole may bethe principal mechanisms of these disorders

impairments in working memory in the mice with the iDGphenotype cannot be excluded

In working memory tasks animals must rapidly establishand maintain a memory of visited areas based on singlewithin-trial exposures and must suppress interference bymemories obtained during previous trials Deficits in eitherfunction could cause impairments in working memory tasksMice with the iDG phenotype commonly display a reductionof frequency facilitation at mossy fibre-CA3 synapses [1ndash3 5] Frequency facilitation is a potential mechanism for the

involvement of the CA3 region in the processing of workingmemory especially in quickly encoding novel informationinto the hippocampal memory system [138] Therefore thedeficit might contribute to impairments in establishmentand maintenance of memory in mice with the iDG phe-notype In addition mice with the iDG phenotype mighthave deficits in processes that reduce memory interferenceInterference between already remembered information andto-be-remembered information can have a profound effecton mnemonic accuracy [139] DG granule cells have been


proposed to play important roles in temporal pattern separa-tion in which an initial event should be separated from a laterevent [140 141] If this hypothesis proves true mice with theiDG phenotype might have deficits in suppressing memoryinterference leading to impaired working memory

92 iDG Pattern Separation and Psychosis Among hip-pocampal subfields computational models have highlightedthe essential role of theDG for disambiguating similar eventsThis so-called pattern separation refers to the computationalprocess for making representations for similar input patternsmore orthogonal for better discrimination [142ndash145] Exper-imental efforts have tested these computational hypothesesusing hippocampal region-selective lesions [146ndash149] in vivoelectrophysiological recording [150] and genetic manipula-tion [151]More recently investigation of adult-bornDGneu-rons in memory formation has focused on specific function-pattern integration and pattern separation [152 153] Marın-Burgin et al showed enhanced excitationinhibition balanceand low input specificity in immature granule cells [153]These electrophysiological features of immature granule cellshave been proposed to be crucial for pattern integration[153] For example mature granule cells are presumably veryselective in their responses which may contribute to patternseparation bymaking the stimulus inputs independent of oneanother In contrast the physiological properties of immaturegranule cells probably make them less selective which mayresult in firing in response to multiple events [152 153]

As mentioned earlier granule cells in the pseudoimma-ture state are hyperexcitable in 120572-CaMKII HKO [1] Shn-2KO [2] SNAP-25KI [3] and FLX-treatedmice [5] Given thatthe physiological properties of pseudoimmature granule cellsare comparable to those of immature granule cells in normaldevelopment it is tempting to hypothesize that due to a lackof appropriatememory separation the iDGphenotype causesexcessive integration and association of memories to actualand imaginary events

However Nakashiba et al have reported that patternseparation requires adult-born immature granule cells notmature granule cells [154] The role of immature and pseu-doimmature granule cells on pattern separationintegrationremains controversialTherefore future studies are needed toexamine input selectivity of pseudoimmature granule cells inmice with the iDG phenotype and to address whether theyexhibit deficits in pattern separation

An iDG signature increased calretinin immunoreactiv-ity has been identified from patients with schizophrenia andbipolar disorderThe increase in the calretinin signal was pos-itively correlated with a history of psychosis in these patients[7] Similarly in iDG mouse models hyperlocomotor activ-ity generally thought to be linked to a hyperdopamin-ergicpsychosis state has been consistently observed [1ndash310] Indeed 120572-CaMKII HKO mice show hyperlocomotionand simultaneously display hypersensitivity to amphetamine-induced hyperlocomotion (Kogan amp Matsumoto unpub-lished observation) a well-established behavioral trait thatis believed to reflect a hyperdopaminergicpsychosis state inpatients with schizophreniabipolar disorder Based on thisevidence iDG may represent a pathophysiological deficit

shared among patients with psychosis a deficit presumablylinked to a hyperdopaminergic state Interestingly iDGsignatures have also been identified in pilocarpine-inducedepilepsy mouse models [6] Epidemiological evidence indi-cates that psychosis is often comorbid with epilepsy and vice-versa [155]Thus these recent findings suggest that a commonhyperdopaminergic state may further strengthen the linkbetween epilepsy and psychosis [156]

How iDG contributes to psychosis and a hyperdopamin-ergic state remains an open question While not fullyanswered iDG may fit as a potential player in the disturbedneurocircuits based on recent studies that have proposed thathippocampal neurocircuits influence dopaminergic neuronaltones that underlie psychotic and schizophrenic conditions[157 158]

The consequences of iDG (specifically excess immatureless-mature granule cells) on the function of the hippocam-pus also remain open questions It has recently been pro-posed that immature granule cells in the DG may inhibitor destabilize activity of the entire DG via activation ofinhibitory GABAergic input from hilar interneurons [159]Because immature granule cells preferentially innervate hilarinterneurons and these interneurons innervate all DG gran-ule cells excess immature neurons may consequently lead togross inhibition of the DG Although immature granule cellsin iDG models are hyperexcitable compared to mature gran-ule cells [1ndash3 5] their hyperexcitability may cause furthergross inhibition of DG by the proposed feedback mechanismfromhilar interneurons A synaptic competition for perforantpath connections between older more-mature granule cellsand newly generated immature cells has also been proposedas a potential cause of the gross inhibition of the DG byimmature granule cells [159] In iDG mouse models maturegranule cells are dramatically reduced This reduction ofmature neurons could be easily connected to dysfunction ofthe DG especially after considering the reduced arborizationof DG granule cells in iDG models [1]

In iDGmodels the DG also does not respond to stimulus(eg lack of c-Fos expression in DG following electric footshock in 120572-CaMKII HKO mice [1] and dramatically reducedArc induction in a novel environment in Shn-2 KOmice [2])It currently remains unclear whether DG activity is actuallydecreased Furthermore it remains unclear if decreased DGactivity leads to less glutamatergic input to CA3 from the DGthrough mossy fibers Although mossy fibers from the DG toCA3 are glutamatergic and come into direct contact with CA3pyramidal neuronsmanymossy fiber synapses are connectedto interneurons in CA3 that provide GABAergic inhibitoryinput to CA3 pyramidal cells As a consequence DG andmossy fiber activation causes a net inhibition within the CA3network and presumably activates only a specific subset ofCA3 pyramidal neurons [160 161] From this vantage pointnet inhibition of the DG by immature granule cells may causea tonic net activation of CA3 Induction of Arc transcriptionafter foot shock was greatly suppressed in almost everyregion of the Shn-2 KO brain Despite this near-ubiquitousreduction of Arc comparable Arc induction was observed inthe CA1 and CA3 regions of the hippocampus in Shn-2 KOand control miceThe relatively higher Arc induction in these


regions suggests that CA areas in these mutant mice may bemore active than other brain regions

This functional failure in the hippocampal formation perse is proposed by Tamminga et al [158] as an underlyingmechanism of psychosis in which hypoactive DG (weakenedpattern separation) and hyperactive CA3 (strengthened pat-tern completion) confer psychosis (cognitive ldquomistakesrdquo) inpatients with schizophrenia and other psychiatric conditionsSince an iDG signature was identified in patients withschizophrenia and bipolar disorder and due to its strongassociation with psychosis it is conceivable that iDG is oneof the potential mechanisms causing dysfunction of the DGand subsequent tonic activation of CA3-CA1 in patients withpsychiatric conditions

As discussed earlier a subcortical hyperdopaminergicstate in patients is also believed to play a pivotal role inthe development of psychosis and is the only biochemicalfinding supported by the mechanism-of-action of currentlyavailable drugs A hypothesis has been proposed by Graceet al [157 162] suggesting that overdrive of the subcorticaldopamine system is caused by hyperactivation of the ventralhippocampus Tonic activation of ventral CA3-CA1 inducedby the iDG phenotype theoretically leads to activation of theventral subiculum (vSub) through direct glutamatergic trans-mission Glutamatergic afferents to the nucleus accumbens(NAc) from the vSub then activate GABAergic projectionsfrom the NAc to the ventral pallidum suppressing pallidalGABAergic efferent neurons Because dopaminergic neuronsin the ventral tegmental area (VTA) that project to thesubcortical limbic region (including the NAc) are governedby GABAergic inhibitory projections from the ventral pal-lidum activation of the NAc by the vSub suppresses tonicinhibitory GABAergic inputs from the ventral pallidum andconsequently leads to tonic activation of VTA dopamineneurons

10 Conclusion

In the course of large-scale behavioral screening of mousemodels of neuropsychiatric disorders a number of strains ofmice displayed a series of schizophrenia-related behavioralabnormalities including increased locomotor activity severeworking memory deficits and decreased social interactionAmong these models 120572-CaMKII HKO Shn-2 KO SNAP-25 KI and CN KO mice all possessed an iDG phenotypeSubsequently it was shown that chronic FLX treatmentor pilocarpine-induced SRS reverses neuronal maturationresulting in the iDG phenotype in wild-type mice Impor-tantly iDG-like phenomena have been observed in the brainsof patients with schizophrenia and bipolar disorder whenexamined postmortem Based on these observations iDGis proposed as a potential endophenotype shared by certaintypes of neuropsychiatric disorders

Due to limitations of the current psychiatric diagnosticmethods schizophrenia bipolar disorder and other relatedpsychiatric disorders are considered biologically heteroge-neous populationsTherefore an endophenotype-based anal-ysis would be preferable for establishing biological character-istics for the classification of psychiatric disorders rather than

an analysis based on current diagnosticmethods [163] In thiscontext the current findings suggest that the iDG phenotypecould be used as a potential brain endophenotype shared byneuropsychiatric disorders (including schizophrenia bipolardisorders and epilepsy) and could be useful for phenotype-based classification of these disorders Furthermore at leastpartial rescue of iDGphenotypes and some behavioral abnor-malities was possible in Shn-2 KO and SNAP-25 KI micewith treatment based on possiblemechanisms underlying theiDGphenotype Further investigation of iDG as an importantfactor in the precipitation of as well as recovery fromepisodes of schizophrenia and other psychiatric disorderswould facilitate the study of these disorders

Disclosure

NoahMWalton andMitsuyukiMatsumoto are employees ofthe Astellas Research Institute of America LLC a subsidiaryof Astellas Pharma Inc The other authors declare no conflictof interests

Acknowledgment

This work was supported by KAKENHI (24111546 2002301718023022 and 17025023) from the Ministry of EducationCulture Sports Science and Technology (MEXT) of JapanPromotion of Fundamental Studies in Health Sciences ofthe National Institute of Biomedical Innovation (NIBIO)Neuroinformatics Japan Center (NIJC) and by grants fromCREST amp BIRD of the Japan Science and TechnologyAgency (JST) The authors gratefully acknowledge HisatsuguKoshimizu in Fujita Health University for his helpful com-ments on the paper

References

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[2] K Takao K Kobayashi H Hagihara et al ldquoDeficiency ofSchnurri-2 an MHC enhancer binding protein induces mildchronic inflammation in the brain and confers molecularneuronal and behavioral phenotypes related to schizophreniardquoNeuropsychopharmacology 2013

[3] K Ohira K Kobayashi K Toyama et al ldquoSynaptosomal-associated protein 25 mutation converts dentate granule cells toan immature state in adult micerdquoMolecular Brain vol 6 article12 2013

[4] H Hagihara H K Nakamura K Toyama I A Graef GR Crabtree and T Miyakawa ldquoForebrain-specific calcineurindeficiency causes immaturity of the dentate granule cells inadult micerdquo SfN meeting 2011 abstract

[5] K Kobayashi Y Ikeda A Sakai et al ldquoReversal of hippocampalneuronal maturation by serotonergic antidepressantsrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 107 no 18 pp 8434ndash8439 2010

[6] R Shin K Kobayashi H Hagihara et al ldquoThe immature den-tate gyrus represents a common endophenotype of psychiatricdisorders and epilepsyrdquo Bipolar Disorders 2013


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[8] K Takao N Yamasaki and T Miyakawa ldquoImpact of brain-behavior phenotypying of genetically-engineered mice onresearch of neuropsychiatric disordersrdquo Neuroscience Researchvol 58 no 2 pp 124ndash132 2007

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[67] S Otsuka S Yamamori S Watanabe et al ldquoPKC-dependentphosphorylation of SNAP-25 plays a crucial role in the sup-pression of epileptogenesis and anxiety-related behavior inpostnatal period of mouserdquo Neuroscience Research vol 71supplement article e296 2011

[68] A Vezzani ldquoInflammation and epilepsyrdquo Epilepsy Currents vol5 no 1 pp 1ndash6 2005

[69] A Vezzani and T Granata ldquoBrain inflammation in epilepsyexperimental and clinical evidencerdquo Epilepsia vol 46 no 11 pp1724ndash1743 2005

[70] O Tomkins O Friedman S Ivens et al ldquoBlood-brain barrierdisruption results in delayed functional and structural alter-ations in the rat neocortexrdquoNeurobiology of Disease vol 25 no2 pp 367ndash377 2007

[71] E A van Vliet S da C Araujo S Redeker R Van Schaik EAronica and J AGorter ldquoBlood-brain barrier leakagemay leadto progression of temporal lobe epilepsyrdquo Brain vol 130 no 2pp 521ndash534 2007


[72] L Uva L Librizzi N Marchi et al ldquoAcute induction ofepileptiform discharges by pilocarpine in the in vitro isolatedguinea-pig brain requires enhancement of blood-brain barrierpermeabilityrdquo Neuroscience vol 151 no 1 pp 303ndash312 2008

[73] P F Fabene G N Mora M Martinello et al ldquoA rolefor leukocyte-endothelial adhesion mechanisms in epilepsyrdquoNature Medicine vol 14 no 12 pp 1377ndash1383 2008

[74] M Zhou W Li S Huang et al ldquomTOR inhibition amelioratescognitive and affective deficits caused by Disc1 knockdown inadult-born dentate granule neuronsrdquo Neuron vol 77 no 4 pp647ndash654 2013

[75] D St Clair D Blackwood W Muir et al ldquoAssociation within afamily of a balanced autosomal translocationwithmajormentalillnessrdquoThe Lancet vol 336 no 8706 pp 13ndash16 1990

[76] N Burnashev H Monyer P H Seeburg and B SakmannldquoDivalent ion permeability of AMPA receptor channels isdominated by the edited form of a single subunitrdquo Neuron vol8 no 1 pp 189ndash198 1992

[77] M Hollmann M Hartley and S Heinemann ldquoCa2+ per-meability of KA-AMPA-gated glutamate receptor channelsdepends on subunit compositionrdquo Science vol 252 no 5007pp 851ndash853 1991

[78] R I Hume R Dingledine and S F Heinemann ldquoIdentificationof a site in glutamate receptor subunits that controls calciumpermeabilityrdquo Science vol 253 no 5023 pp 1028ndash1031 1991

[79] C ZhaoW Deng and F H Gage ldquoMechanisms and functionalimplications of adult neurogenesisrdquoCell vol 132 no 4 pp 645ndash660 2008

[80] S Jessberger and G Kempermann ldquoAdult-born hippocampalneurons mature into activity-dependent responsivenessrdquo TheEuropean Journal of Neuroscience vol 18 no 10 pp 2707ndash27122003

[81] P S Goldman-Rakic ldquoWorking memory dysfunction inschizophreniardquo Journal of Neuropsychiatry and Clinical Neuro-sciences vol 6 no 4 pp 348ndash357 1994

[82] B Elvevag and T E Goldberg ldquoCognitive impairment inschizophrenia is the core of the disorderrdquo Critical Reviews inNeurobiology vol 14 no 1 pp 1ndash21 2000

[83] D L Braff and M A Geyer ldquoSensorimotor gating andschizophrenia human and animal model studiesrdquo Archives ofGeneral Psychiatry vol 47 no 2 pp 181ndash188 1990

[84] American Psychiatric Association Diagnostic and StatisticalManual of Mental Disorders American Psychiatric AssociationWashington DC USA 4th edition 1994

[85] R R Gainetdinov A R Mohn L M Bohn and M G CaronldquoGlutamatergic modulation of hyperactivity in mice lacking thedopamine transporterrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 98 no 20 pp 11047ndash11054 2001

[86] P R Maycox F Kelly A Taylor et al ldquoAnalysis of gene expres-sion in two large schizophrenia cohorts identifies multiplechanges associated with nerve terminal functionrdquo MolecularPsychiatry vol 14 no 12 pp 1083ndash1094 2009

[87] Z J Zhang and G P Reynolds ldquoA selective decrease in therelative density of parvalbumin-immunoreactive neurons in thehippocampus in schizophreniardquo Schizophrenia Research vol 55no 1-2 pp 1ndash10 2002

[88] M B Knable B M Barci M J Webster J Meador-Woodruffand E F Torrey ldquoMolecular abnormalities of the hippocampusin severe psychiatric illness postmortem findings from theStanley Neuropathology Consortiumrdquo Molecular Psychiatryvol 9 no 6 pp 609ndash620 2004

[89] F M Benes B Lim D Matzilevich J P Walsh S Subburajuand M Minns ldquoRegulation of the GABA cell phenotype inhippocampus of schizophrenics and bipolarsrdquoProceedings of theNational Academy of Sciences of theUnited States of America vol104 no 24 pp 10164ndash10169 2007

[90] J N Pierri A S Chaudry T U W Woo and D A LewisldquoAlterations in chandelier neuron axon terminals in the pre-frontal cortex of schizophrenic subjectsrdquoThe American Journalof Psychiatry vol 156 no 11 pp 1709ndash1719 1999

[91] J Gallinat G Winterer C S Herrmann and D SenkowskildquoReduced oscillatory gamma-band responses in unmedicatedschizophrenic patients indicate impaired frontal network pro-cessingrdquo Clinical Neurophysiology vol 115 no 8 pp 1863ndash18742004

[92] L V Moran and L E Hong ldquoHigh vs low frequency neuraloscillations in schizophreniardquo Schizophrenia Bulletin vol 37 no4 pp 659ndash663 2011

[93] S R Sponheim B A Clementz W G Iacono and M BeiserldquoResting EEG in first-episode and chronic schizophreniardquoPsychophysiology vol 31 no 1 pp 37ndash43 1994

[94] A Abi-Dargham ldquoDo we still believe in the dopamine hypoth-esis New data bring new evidencerdquoThe International Journal ofNeuropsychopharmacology vol 7 supplement 1 pp S1ndashS5 2004

[95] G Winterer and D R Weinberger ldquoGenes dopamine andcortical signal-to-noise ratio in schizophreniardquo Trends in Neu-roscience vol 27 no 11 pp 683ndash690 2004

[96] D A Cousins K Butts andAH Young ldquoThe role of dopaminein bipolar disorderrdquoBipolar Disorders vol 11 no 8 pp 787ndash8062009

[97] G Novak and P Seeman ldquoHyperactive mice show ele-vated D2High receptors a model for schizophrenia calciumcalmodulin-dependent kinase II alpha knockoutsrdquo Synapse vol64 no 10 pp 794ndash800 2010

[98] C R Maxwell S J Kanes T Abel and S J Siegel ldquoPhos-phodiesterase inhibitors a novel mechanism for receptor-independent antipsychotic medicationsrdquoNeuroscience vol 129no 1 pp 101ndash107 2004

[99] S J Kanes J Tokarczyk S J Siegel W Bilker T Abel andM PKelly ldquoRolipram a specific phosphodiesterase 4 inhibitor withpotential antipsychotic activityrdquoNeuroscience vol 144 no 1 pp239ndash246 2007

[100] J Lisman H Schulman and H Cline ldquoThe molecular basis ofCaMKII function in synaptic and behavioural memoryrdquoNatureReviews Neuroscience vol 3 no 3 pp 175ndash190 2002

[101] D R Weinberger ldquoImplications of normal brain developmentfor the pathogenesis of schizophreniardquo Archives of GeneralPsychiatry vol 44 no 7 pp 660ndash669 1987

[102] D R Weinberger and R K McClure ldquoNeurotoxicity neuro-plasticity andmagnetic resonance imagingmorphometry whatis happening in the schizophrenic brainrdquo Archives of GeneralPsychiatry vol 59 no 6 pp 553ndash558 2002

[103] S Marenco and D R Weinberger ldquoThe neurodevelopmentalhypothesis of schizophrenia following a trail of evidence fromcradle to graverdquo Development and Psychopathology vol 12 no3 pp 501ndash527 2000

[104] T D Cannon I M Rosso C E Bearden L E Sanchez andT Hadley ldquoA prospective cohort study of neurodevelopmentalprocesses in the genesis and epigenesis of schizophreniardquoDevelopment and Psychopathology vol 11 no 3 pp 467ndash4851999


[105] B K Lipska ldquoUsing animal models to test a neurodevelop-mental hypothesis of schizophreniardquo Journal of Psychiatry andNeuroscience vol 29 no 4 pp 282ndash286 2004

[106] C T Ekdahl J-H Claasen S Bonde Z Kokaia andO LindvallldquoInflammation is detrimental for neurogenesis in adult brainrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 23 pp 13632ndash13637 2003

[107] S Das and A Basu ldquoInflammation a new candidate in modu-lating adult neurogenesisrdquo Journal of Neuroscience Research vol86 no 6 pp 1199ndash1208 2008

[108] R L Hunter N Dragicevic K Seifert et al ldquoInflammationinduces mitochondrial dysfunction and dopaminergic neu-rodegeneration in the nigrostriatal systemrdquo Journal of Neuro-chemistry vol 100 no 5 pp 1375ndash1386 2007

[109] M T Fischer R Sharma J L Lim et al ldquoNADPH oxidaseexpression in active multiple sclerosis lesions in relation tooxidative tissue damage and mitochondrial injuryrdquo Brain vol135 no 3 pp 886ndash899 2012

[110] Y Pang Z Cai and P G Rhodes ldquoDisturbance of oligo-dendrocyte development hypomyelination and white matterinjury in the neonatal rat brain after intracerebral injection oflipopolysacchariderdquoDevelopmental Brain Research vol 140 no2 pp 205ndash214 2003

[111] W Bruck R Pfortner T Pham et al ldquoReduced astrocytic NF-120581B activation by laquinimod protects from cuprizone-induceddemyelinationrdquo Acta Neuropathologica vol 124 no 3 pp 411ndash424 2012

[112] A Reif S Fritzen M Finger et al ldquoNeural stem cell prolif-eration is decreased in schizophrenia but not in depressionrdquoMolecular Psychiatry vol 11 no 5 pp 514ndash522 2006

[113] M S Keshavan H A Nasrallah and R Tandon ldquoSchizophre-nia ldquoJust the Factsrdquo 6 Moving ahead with the schizophre-nia concept from the elephant to the mouserdquo SchizophreniaResearch vol 127 no 1ndash3 pp 3ndash13 2011

[114] H Nawa and N Takei ldquoRecent progress in animal modeling ofimmune inflammatory processes in schizophrenia implicationof specific cytokinesrdquo Neuroscience Research vol 56 no 1 pp2ndash13 2006

[115] P H Patterson ldquoImmune involvement in schizophrenia andautism etiology pathology and animal modelsrdquo BehaviouralBrain Research vol 204 no 2 pp 313ndash321 2009

[116] A S Brown and P H Patterson ldquoMaternal infection andschizophrenia implications for preventionrdquo Schizophrenia Bul-letin vol 37 no 2 pp 284ndash290 2011

[117] E Y Hsiao S W McBride J Chow S K Mazmanian and PH Patterson ldquoModeling an autism risk factor in mice leads topermanent immune dysregulationrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 109 no31 pp 12776ndash12781 2012

[118] P H Patterson ldquoMaternal infection window on neuroimmuneinteractions in fetal brain development and mental illnessrdquoCurrent Opinion in Neurobiology vol 12 no 1 pp 115ndash118 2002

[119] L Shi SH Fatemi RW Sidwell and PH Patterson ldquoMaternalinfluenza infection causes marked behavioral and pharmaco-logical changes in the offspringrdquo The Journal of Neurosciencevol 23 no 1 pp 297ndash302 2003

[120] J P A Ioannidis E E Ntzani T A Trikalinos and D GContopoulos-Ioannidis ldquoReplication validity of genetic associ-ation studiesrdquoNature Genetics vol 29 no 3 pp 306ndash309 2001

[121] M Ayalew H Le-Niculescu D F Levey et al ldquoConvergentfunctional genomics of schizophrenia from comprehensive

understanding to genetic risk predictionrdquoMolecular Psychiatryvol 17 no 9 pp 887ndash905 2012

[122] K V Chowdari K Mirnics P Semwal et al ldquoAssociation andlinkage analyses of RGS4 polymorphisms in schizophreniardquoHuman Molecular Genetics vol 11 no 12 pp 1373ndash1380 2002

[123] K Mirnics F A Middleton G D Stanwood D A Lewis andP Levitt ldquoDisease-specific changes in regulator of G-proteinsignaling 4 (RGS4) expression in schizophreniardquo MolecularPsychiatry vol 6 no 3 pp 293ndash301 2001

[124] T L Petryshen F A Middleton A R Tahl et al ldquoGeneticinvestigation of chromosome 5q GABAA receptor subunitgenes in schizophreniardquoMolecular Psychiatry vol 10 no 12 pp1074ndash1088 2005

[125] N C Allen S Bagade M B McQueen et al ldquoSystematic meta-analyses and field synopsis of genetic association studies inschizophrenia the SzGene databaserdquo Nature Genetics vol 40no 7 pp 827ndash834 2008

[126] S J Huffaker J Chen K K Nicodemus et al ldquoA primate-specific brain isoform of KCNH2 affects cortical physiologycognition neuronal repolarization and risk of schizophreniardquoNature Medicine vol 15 no 5 pp 509ndash518 2009

[127] R Zakharyan A Khoyetsyan A Arakelyan et al ldquoAssociationof C1QB gene polymorphism with schizophrenia in Armenianpopulationrdquo BMCMedical Genetics vol 12 article 126 2011

[128] J Ekelund D Lichtermann I Hovatta et al ldquoGenome-widescan for schizophrenia in the Finnish population evidence fora locus on chromosome 7q22rdquo Human Molecular Genetics vol9 no 7 pp 1049ndash1057 2000

[129] W Yan X-Y Guan E D Green et al ldquoChildhood-onsetschizophreniaautistic disorder and t(17) reciprocal transloca-tion identification of a BAC contig spanning the translocationbreakpoint at 7q21rdquo American Journal of Medical Genetics vol96 no 6 pp 749ndash753 2000

[130] M Bradford M H Law A D Stewart D J Shaw I L Megsonand J Wei ldquoThe TGM2 gene is associated with schizophreniain a british populationrdquo American Journal of Medical GeneticsB vol 150 no 3 pp 335ndash340 2009

[131] S W Flynn D J Lang A L Mackay et al ldquoAbnormalitiesof myelination in schizophrenia detected in vivo with MRIand post-mortem with analysis of oligodendrocyte proteinsrdquoMolecular Psychiatry vol 8 no 9 pp 811ndash820 2003

[132] K Iwamoto M Bundo and T Kato ldquoAltered expression ofmitochondria-related genes in postmortem brains of patientswith bipolar disorder or schizophrenia as revealed by large-scale DNA microarray analysisrdquo Human Molecular Geneticsvol 14 no 2 pp 241ndash253 2005

[133] D S Olton and B C Papas ldquoSpatial memory and hippocampalfunctionrdquo Neuropsychologia vol 17 no 6 pp 669ndash682 1979

[134] P S Goldman-Rakic ldquoRegional and cellular fractionation ofworking memoryrdquo Proceedings of the National Academy ofSciences of the United States of America vol 93 no 24 pp13473ndash13480 1996

[135] R L McLamb W R Mundy and H A Tilson ldquoIntradentatecolchicine disrupts the acquisition and performance of a work-ing memory task in the radial armmazerdquo NeuroToxicology vol9 no 3 pp 521ndash528 1988

[136] D F Emerich and T J Walsh ldquoSelective working memoryimpairments following intradentate injection of colchicineattenuation of the behavioral but not the neuropathologicaleffects by gangliosides GM1 and AGF2rdquo Physiology amp Behaviorvol 45 no 1 pp 93ndash101 1989


[137] A M Morris J C Churchwell R P Kesner and P E GilbertldquoSelective lesions of the dentate gyrus produce disruptions inplace learning for adjacent spatial locationsrdquo Neurobiology ofLearning and Memory vol 97 no 3 pp 326ndash331 2012

[138] R P Kesner ldquoBehavioral functions of the CA3 subregion of thehippocampusrdquoLearning andMemory vol 14 no 11 pp 771ndash7812007

[139] M L Shapiro andD S OltonMemory Systems 1994 MIT Press1994

[140] J B Aimone J Wiles and F H Gage ldquoPotential role for adultneurogenesis in the encoding of time in newmemoriesrdquoNatureNeuroscience vol 9 no 6 pp 723ndash727 2006

[141] M A Yassa and C E L Stark ldquoPattern separation in thehippocampusrdquo Trends in Neurosciences vol 34 no 10 pp 515ndash525 2011

[142] D Marr ldquoSimple memory a theory for archicortexrdquo Philosoph-ical Transactions of the Royal Society of London B vol 262 no841 pp 23ndash81 1971

[143] B LMcNaughton and R GMMorris ldquoHippocampal synapticenhancement and information storage within a distributedmemory systemrdquo Trends in Neurosciences vol 10 no 10 pp408ndash415 1987

[144] R C OrsquoReilly and J L McClelland ldquoHippocampal conjunctiveencoding storage and recall avoiding a trade-offrdquo Hippocam-pus vol 4 no 6 pp 661ndash682 1994

[145] A Treves A Tashiro M EWitter and E I Moser ldquoWhat is themammalian dentate gyrus good forrdquoNeuroscience vol 154 no4 pp 1155ndash1172 2008

[146] P E Gilbert R P Kesner and I Lee ldquoDissociating hippocampalsubregions a double dissociation between dentate gyrus andCA1rdquo Hippocampus vol 11 no 6 pp 626ndash636 2001

[147] P E Gilbert and R P Kesner ldquoLocalization of function withinthe dorsal hippocampus the role of the CA3 subregion inpaired-associate learningrdquo Behavioral Neuroscience vol 117 no6 pp 1385ndash1394 2003

[148] I Lee and R P Kesner ldquoDifferent contributions of dorsalhippocampal subregios to emory acquisation and retrieval incontextual fear-conditioningrdquo Hippocampus vol 14 no 3 pp301ndash310 2004

[149] I Lee and R P Kesner ldquoEncoding versus retrieval of spatialmemory double dissociation between the dentate gyrus andthe perforant path inputs into CA3 in the dorsal hippocampusrdquoHippocampus vol 14 no 1 pp 66ndash76 2004

[150] J K Leutgeb S Leutgeb M-B Moser and E I Moser ldquoPatternseparation in the dentate gyrus and CA3 of the hippocampusrdquoScience vol 315 no 5814 pp 961ndash966 2007

[151] T J McHugh M W Jones J J Quinn et al ldquoDentate gyrusNMDA receptors mediate rapid pattern separation in thehippocampal networkrdquo Science vol 317 no 5834 pp 94ndash992007

[152] J B Aimone W Deng and F H Gage ldquoResolving new memo-ries a critical look at the dentate gyrus adult neurogenesis andpattern separationrdquo Neuron vol 70 no 4 pp 589ndash596 2011

[153] A Marın-Burgin L A Mongiat M B Pardi and A FSchinder ldquoUnique processing during a period of high excita-tioninhibition balance in adult-bornneuronsrdquo Science vol 335no 6073 pp 1238ndash1242 2012

[154] T Nakashiba J D Cushman K A Pelkey et al ldquoYoung dentategranule cells mediate pattern separation whereas old granulecells facilitate pattern completionrdquo Cell vol 149 no 1 pp 188ndash201 2012

[155] W A M Swinkels J Kuyk R van Dyck and P SpinhovenldquoPsychiatric comorbidity in epilepsyrdquo Epilepsy and Behaviorvol 7 no 1 pp 37ndash50 2005

[156] P Cifelli and A A Grace ldquoPilocarpine-induced temporal lobeepilepsy in the rat is associatedwith increased dopamineneuronactivityrdquo The International Journal of Neuropsychopharmacol-ogy vol 15 no 7 pp 957ndash964 2012

[157] D J Lodge and A A Grace ldquoHippocampal dysregulationof dopamine system function and the pathophysiology ofschizophreniardquo Trends in Pharmacological Sciences vol 32 no9 pp 507ndash513 2011

[158] C A Tamminga S Southcott C Sacco A D Wagner and SGhose ldquoGlutamate dysfunction in hippocampus relevance ofdentate gyrus and CA3 signalingrdquo Schizophrenia Bulletin vol38 no 5 pp 927ndash935 2012

[159] C O Lacefield V Itskov T Reardon R Hen and J A Gor-don ldquoEffects of adult-generated granule cells on coordinatednetwork activity in the dentate gyrusrdquoHippocampus vol 22 no1 pp 106ndash116 2012

[160] D A Henze N N Urban and G Barrionuevo ldquoThe multifari-ous hippocampal mossy fiber pathway a reviewrdquo Neurosciencevol 98 no 3 pp 407ndash427 2000

[161] J Song K M Christian G Ming and H Song ldquoModificationof hippocampal circuitry by adult neurogenesisrdquoDevelopmentalNeurobiology vol 72 no 7 pp 1032ndash1043 2012

[162] A A Grace S B Floresco Y Goto andD J Lodge ldquoRegulationof firing of dopaminergic neurons and control of goal-directedbehaviorsrdquo Trends in Neurosciences vol 30 no 5 pp 220ndash2272007

[163] I I Gottesman and T D Gould ldquoThe endophenotype conceptin psychiatry etymology and strategic intentionsrdquo The Ameri-can Journal of Psychiatry vol 160 no 4 pp 636ndash645 2003

Submit your manuscripts athttpwwwhindawicom

Neurology Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


BioMed Research International


Research and TreatmentSchizophrenia

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


Neural Plasticity


Parkinsonrsquos Disease


Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Neuroscience Journal

Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Psychiatry Journal


Computational and Mathematical Methods in Medicine

Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Brain ScienceInternational Journal of

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases


Journal of

Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

2 Neural Plasticity

Body weight

Rectal temperature

Grip strength

Anxiety-like behaviorActivity

Motor coordinationPain sensitivity

Prepulse inhibition

Depression-like behaviorWorking memory

Reference memory

Social interaction(novel environment)

Social interaction(home cage)

Increased 119875 lt 0001Increased 119875 lt 001

Increased 119875 lt 005




Figure 1 Heat map showing behavioral phenotypes of more than 160 strains of genetically engineered mice Each column represents themouse strain analyzed in the laboratory of the authorrsquos group (unpublished data) Each row represents a behavior category assessed by thecomprehensive battery of behavioral tests Colors represent an increase (red) or decrease (green) compared between wild-type and mutantmice Adapted from Takao et al [8]

quite similar to the iDG phenotype identified in thesemutantmice has also been found in mice treated with chronicfluoxetine [5] and in a pilocarpine-induced mouse model ofepilepsy [6] Moreover postmortem analysis for molecularmarkers of neuronal maturity in the DG revealed an iDG-like signature for brains of patients with schizophrenia andbipolar disorder [7]

The purpose of this review is to introduce how theiDG phenotype was identified and its molecular and cellularsignature An additional goal is to summarize potentialmechanisms underlying the iDG phenotype and its impacton brain functions

2 Discovery of iDG in 120572-CaMKII HKO Mice

A high-throughput comprehensive behavioral testing batterywas developed for many different strains of geneticallyengineered mice The battery of tests covers many behavioraldomains ranging from sensorimotor functions to highlycognitive functions like learning and memory In the courseof a large-scale effort to phenotype the genetically engineeredmice (mutant mice) this battery of tests was administeredto more than 160 strains of knockout and transgenic mice(Figure 1) [8] Surprisingly when tested most of the strains ofmutant mice displayed at least some aberrant behavioral phe-notypes whichmay suggest that many of the genes expressedin the brain may have some functional significance at thebehavior level In the course of screening the mutant micepopulations a number of mouse strains were identified thatshowed abnormal behaviors common to neuropsychiatricdisorders (eg schizophrenia bipolar disorder and autism)Among these mutant mouse models the 120572-CaMKII HKOmice showed a particularly dramatic series of abnormalbehaviorsThe first discovery of the iDG phenotype occurredduring investigations into the neuropathophysiology under-lying these behaviors

Calmodulin-dependent protein kinase II (CaMKII) isa major downstream molecule of the N-methyl-d-asparticacid (NMDA) receptor which has presumed involvement inthe pathophysiology of schizophrenia The function of theNMDA receptor can bemodulated by calcineurin a potentialsusceptibility gene we previously identified [9 10] CaMKII isthought to play an essential role in neural plasticity such aslong-term potentiation and long-term depression [11]

Perhaps the most striking behavioral phenotype of 120572-CaMKII HKO mice is that they occasionally kill their cagemates (often littermates) Prior to 6months of age120572-CaMKIIHKO mice kill more than half of their group-housed cagemates In addition these mice show greatly increased loco-motor activity in the open field test While 120572-CaMKII HKOmice demonstrate normal reference memory as assessed bythe reference memory version of the eight-arm radial mazetest their working memory is severely impaired Likewisein the T-maze forced-alternation test the working memoryof the 120572-CaMKII HKO mice was found to be severelyimpaired while they showed normal performance in a simpleleftright discrimination task using the same apparatusesPrevious studies have presented representative videos of theperformance of 120572-CaMKII HKO mice in these tasks [12]Using the home cage locomotor activity monitoring systemwhich measures distance travelled in the home cage it wasshown that the locomotor activity patterns of the 120572-CaMKIIHKO mice slowly and dramatically change over time Thesemice show a periodic mood-change-like behavior in theirhome cage (Figure 2(a)) and 1 cycle lasts approximately 10ndash20 d The manifestations of this behavioral phenotype are soclear that these mutant mice can be easily identified usingthese activity patterns

The next task was to understand the underlying patho-physiology in the brains of the 120572-CaMKII mutants thatshow this dramatic array of behavioral abnormalities Firsta transcriptome analysis of the hippocampus of mutant mice

Neural Plasticity 3

Time (day)

Dist

ance

trav

eled

(au

)

0

400

0

400

0

400

5 10 15 20 25 30 35

40 45 50 55 60 65

75 80 85 90Time (day)

Dist

ance

trav

eled

(au

)

0

400

0

400

0

400

5 10 15 20 25 30 35

40 45 50 55 60 65 70

75 80 85 90

Wild-type



70

120572-CaMKII HKO

(a)


Nephronectin






Relat

ive e

xpre

ssio

nRe

lativ

e exp

ress

ion

Relat

ive e

xpre

ssio

nRe

lativ

e exp

ress

ion

Relat

ive e

xpre

ssio

nRe

lativ

e exp

ress

ion

543210

56

43210

2

15

1

05

0

2

15

1

05

0

15

1

05

0

08

06

04

02

0

(b)


PSA-NCAM Calretinin

PSA-NCAM Calretinin

Calbindin

Calbindin

120572-CaMKII HKO

Wild-type

(c)


200 120583m

(d)


4 Neural Plasticity












Neural Plasticity 5


4

5

6

7

8


Diff

eren

t arm

choi

ce in

firs

t 8 en

trie

s

lowastlowast

lowast

lowastlowast


Wild-type (119899 = 16)Shn-2 KO (119899 = 10)

(a)


Blocks of 2 trials

0

5

10

15

20

25

3 6 9 12

lowast lowast

lowast lowastlowast

lowast lowast

Revi

sitin

g er

rors

Wild-type (119899 = 16)Shn-2 KO (119899 = 10)

(b)

T-maze test

50

60

70

80

90

100

02 4 6 8

Cor

rect

resp

onse

s (

)

Sessions

lowast lowastlowast

Wild-type (119899 = 16)Shn-2 KO (119899 = 7)


(c)

0

20

40

60

80

100

2 4 6 8 10 12 14Sessions


Reversal

Cor

rect

resp

onse

s (

)

Wild-type (119899 = 16)Shn-2 KO (119899 = 5)

(d)



124=45597




7147= 3273 119875 = 00029)




6 Neural Plasticity

0

1

2

3

4

5

0 1 2 3 4 5 6

120572-C

aMKI

I HKO

mic

e (fo

ld ch

ange

)


119903 = 081 (119875 lt 00001)

(a)

Wild-type


Shn-2 KOWild-type

A130090K04RikWnk4

Ccnd1Fbxo7Unc5d

MGI1930803Spata13

LOC547362Nhlh1

Acvr1c

0 1 2 3 4 5

Ryr1Tspan18Pcdh21

Marcksl1

Capn3Calb1NpntDsp

Tdo2

0 05 1

0 1 2 3 4 5 6 7

0 05 1

120572-CaMKII HKO

1460043 at

(b)

Calbindin

Calretinin

Wild-type Shn-2 KO

Wild-type Shn-2 KO

500 120583m

250 120583m

(c)




Neural Plasticity 7











8 Neural Plasticity

0

1

2

3Re

lativ

e exp

ress

ion



lowastlowast



(a)

0

05

1

15

2Shn-2 KO mice

Rela

tive e

xpre

ssio

nShn-2 KO


Control


(b)

0

2

4

6

8


Rela

tive e

xpre

ssio

n

FLX

lowastlowast


Control


(c)

0

1

2

3

4

5

6


Rela

tive e

xpre

ssio

n

lowastlowast


PilocarpineControl


(d)




Neural Plasticity 9



Shn-2 KO[2]

SNAP-25KI [3]

CN KO[4 10 21]

FLXtreatment [5]












Molecularphenotypes


























LPS

treat

men

t (fo

ld ch

ange

)Pr

ion

infe

ctio

n (fo

ld ch

ange

)

Agi

ng (f

old

chan

ge)

Inju

ry (f

old

chan

ge)





01

1

10

0 1 2 301

1

10

100

0 1 2 3

01

1

10

100

0 1 2 30

1

2

3

4

0 1 2 3 4

(a)

(b)(f)(e)

(d)(c)

0

1

2

3

0 1 2

34 genes

42 genes 16 genes

8 genes

Schi

zoph

reni

a (fo

ld ch

ange

)


lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast


Fold change



158153CbIn4Tgm2Ma12

Sic14a1Mthfd2

GfapRgs4

D0H4S114Fbxo9Syn2


RP11ndash35N61Gng4




Serpina3nC1qbC1qc

C10orf10Rgs4

Ifitm2C1qaMyt1lTac1

CebpdFrzb

Ifitm1

Ifitm1

Tgfbr1Frzb

Ddit4
































































iDG






Decreased PPI


Model mice



Decreased PPI

Social withdrawal


Causes











Chronic SSRI


Chronic SSRI























10 Conclusion




Disclosure


Acknowledgment


References























































































































































































Neural Plasticity










Psychiatry Journal









Journal of


Neural Plasticity 3

Time (day)

Dist

ance

trav

eled

(au

)

0

400

0

400

0

400

5 10 15 20 25 30 35

40 45 50 55 60 65

75 80 85 90Time (day)

Dist

ance

trav

eled

(au

)

0

400

0

400

0

400

5 10 15 20 25 30 35

40 45 50 55 60 65 70

75 80 85 90

Wild-type



70

120572-CaMKII HKO

(a)


Nephronectin






Relat

ive e

xpre

ssio

nRe

lativ

e exp

ress

ion

Relat

ive e

xpre

ssio

nRe

lativ

e exp

ress

ion

Relat

ive e

xpre

ssio

nRe

lativ

e exp

ress

ion

543210

56

43210

2

15

1

05

0

2

15

1

05

0

15

1

05

0

08

06

04

02

0

(b)


PSA-NCAM Calretinin

PSA-NCAM Calretinin

Calbindin

Calbindin

120572-CaMKII HKO

Wild-type

(c)


200 120583m

(d)


4 Neural Plasticity












Neural Plasticity 5


4

5

6

7

8


Diff

eren

t arm

choi

ce in

firs

t 8 en

trie

s

lowastlowast

lowast

lowastlowast


Wild-type (119899 = 16)Shn-2 KO (119899 = 10)

(a)


Blocks of 2 trials

0

5

10

15

20

25

3 6 9 12

lowast lowast

lowast lowastlowast

lowast lowast

Revi

sitin

g er

rors

Wild-type (119899 = 16)Shn-2 KO (119899 = 10)

(b)

T-maze test

50

60

70

80

90

100

02 4 6 8

Cor

rect

resp

onse

s (

)

Sessions

lowast lowastlowast

Wild-type (119899 = 16)Shn-2 KO (119899 = 7)


(c)

0

20

40

60

80

100

2 4 6 8 10 12 14Sessions


Reversal

Cor

rect

resp

onse

s (

)

Wild-type (119899 = 16)Shn-2 KO (119899 = 5)

(d)



124=45597




7147= 3273 119875 = 00029)




6 Neural Plasticity

0

1

2

3

4

5

0 1 2 3 4 5 6

120572-C

aMKI

I HKO

mic

e (fo

ld ch

ange

)


119903 = 081 (119875 lt 00001)

(a)

Wild-type


Shn-2 KOWild-type

A130090K04RikWnk4

Ccnd1Fbxo7Unc5d

MGI1930803Spata13

LOC547362Nhlh1

Acvr1c

0 1 2 3 4 5

Ryr1Tspan18Pcdh21

Marcksl1

Capn3Calb1NpntDsp

Tdo2

0 05 1

0 1 2 3 4 5 6 7

0 05 1

120572-CaMKII HKO

1460043 at

(b)

Calbindin

Calretinin

Wild-type Shn-2 KO

Wild-type Shn-2 KO

500 120583m

250 120583m

(c)




Neural Plasticity 7











8 Neural Plasticity

0

1

2

3Re

lativ

e exp

ress

ion



lowastlowast



(a)

0

05

1

15

2Shn-2 KO mice

Rela

tive e

xpre

ssio

nShn-2 KO


Control


(b)

0

2

4

6

8


Rela

tive e

xpre

ssio

n

FLX

lowastlowast


Control


(c)

0

1

2

3

4

5

6


Rela

tive e

xpre

ssio

n

lowastlowast


PilocarpineControl


(d)




Neural Plasticity 9



Shn-2 KO[2]

SNAP-25KI [3]

CN KO[4 10 21]

FLXtreatment [5]












Molecularphenotypes


























LPS

treat

men

t (fo

ld ch

ange

)Pr

ion

infe

ctio

n (fo

ld ch

ange

)

Agi

ng (f

old

chan

ge)

Inju

ry (f

old

chan

ge)





01

1

10

0 1 2 301

1

10

100

0 1 2 3

01

1

10

100

0 1 2 30

1

2

3

4

0 1 2 3 4

(a)

(b)(f)(e)

(d)(c)

0

1

2

3

0 1 2

34 genes

42 genes 16 genes

8 genes

Schi

zoph

reni

a (fo

ld ch

ange

)


lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast


Fold change



158153CbIn4Tgm2Ma12

Sic14a1Mthfd2

GfapRgs4

D0H4S114Fbxo9Syn2


RP11ndash35N61Gng4




Serpina3nC1qbC1qc

C10orf10Rgs4

Ifitm2C1qaMyt1lTac1

CebpdFrzb

Ifitm1

Ifitm1

Tgfbr1Frzb

Ddit4
































































iDG






Decreased PPI


Model mice



Decreased PPI

Social withdrawal


Causes











Chronic SSRI


Chronic SSRI























10 Conclusion




Disclosure


Acknowledgment


References























































































































































































Neural Plasticity










Psychiatry Journal









Journal of


4 Neural Plasticity












Neural Plasticity 5


4

5

6

7

8


Diff

eren

t arm

choi

ce in

firs

t 8 en

trie

s

lowastlowast

lowast

lowastlowast


Wild-type (119899 = 16)Shn-2 KO (119899 = 10)

(a)


Blocks of 2 trials

0

5

10

15

20

25

3 6 9 12

lowast lowast

lowast lowastlowast

lowast lowast

Revi

sitin

g er

rors

Wild-type (119899 = 16)Shn-2 KO (119899 = 10)

(b)

T-maze test

50

60

70

80

90

100

02 4 6 8

Cor

rect

resp

onse

s (

)

Sessions

lowast lowastlowast

Wild-type (119899 = 16)Shn-2 KO (119899 = 7)


(c)

0

20

40

60

80

100

2 4 6 8 10 12 14Sessions


Reversal

Cor

rect

resp

onse

s (

)

Wild-type (119899 = 16)Shn-2 KO (119899 = 5)

(d)



124=45597




7147= 3273 119875 = 00029)




6 Neural Plasticity

0

1

2

3

4

5

0 1 2 3 4 5 6

120572-C

aMKI

I HKO

mic

e (fo

ld ch

ange

)


119903 = 081 (119875 lt 00001)

(a)

Wild-type


Shn-2 KOWild-type

A130090K04RikWnk4

Ccnd1Fbxo7Unc5d

MGI1930803Spata13

LOC547362Nhlh1

Acvr1c

0 1 2 3 4 5

Ryr1Tspan18Pcdh21

Marcksl1

Capn3Calb1NpntDsp

Tdo2

0 05 1

0 1 2 3 4 5 6 7

0 05 1

120572-CaMKII HKO

1460043 at

(b)

Calbindin

Calretinin

Wild-type Shn-2 KO

Wild-type Shn-2 KO

500 120583m

250 120583m

(c)




Neural Plasticity 7











8 Neural Plasticity

0

1

2

3Re

lativ

e exp

ress

ion



lowastlowast



(a)

0

05

1

15

2Shn-2 KO mice

Rela

tive e

xpre

ssio

nShn-2 KO


Control


(b)

0

2

4

6

8


Rela

tive e

xpre

ssio

n

FLX

lowastlowast


Control


(c)

0

1

2

3

4

5

6


Rela

tive e

xpre

ssio

n

lowastlowast


PilocarpineControl


(d)




Neural Plasticity 9



Shn-2 KO[2]

SNAP-25KI [3]

CN KO[4 10 21]

FLXtreatment [5]












Molecularphenotypes


























LPS

treat

men

t (fo

ld ch

ange

)Pr

ion

infe

ctio

n (fo

ld ch

ange

)

Agi

ng (f

old

chan

ge)

Inju

ry (f

old

chan

ge)





01

1

10

0 1 2 301

1

10

100

0 1 2 3

01

1

10

100

0 1 2 30

1

2

3

4

0 1 2 3 4

(a)

(b)(f)(e)

(d)(c)

0

1

2

3

0 1 2

34 genes

42 genes 16 genes

8 genes

Schi

zoph

reni

a (fo

ld ch

ange

)


lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast


Fold change



158153CbIn4Tgm2Ma12

Sic14a1Mthfd2

GfapRgs4

D0H4S114Fbxo9Syn2


RP11ndash35N61Gng4




Serpina3nC1qbC1qc

C10orf10Rgs4

Ifitm2C1qaMyt1lTac1

CebpdFrzb

Ifitm1

Ifitm1

Tgfbr1Frzb

Ddit4
































































iDG






Decreased PPI


Model mice



Decreased PPI

Social withdrawal


Causes











Chronic SSRI


Chronic SSRI























10 Conclusion




Disclosure


Acknowledgment


References























































































































































































Neural Plasticity










Psychiatry Journal









Journal of


Neural Plasticity 5


4

5

6

7

8


Diff

eren

t arm

choi

ce in

firs

t 8 en

trie

s

lowastlowast

lowast

lowastlowast


Wild-type (119899 = 16)Shn-2 KO (119899 = 10)

(a)


Blocks of 2 trials

0

5

10

15

20

25

3 6 9 12

lowast lowast

lowast lowastlowast

lowast lowast

Revi

sitin

g er

rors

Wild-type (119899 = 16)Shn-2 KO (119899 = 10)

(b)

T-maze test

50

60

70

80

90

100

02 4 6 8

Cor

rect

resp

onse

s (

)

Sessions

lowast lowastlowast

Wild-type (119899 = 16)Shn-2 KO (119899 = 7)


(c)

0

20

40

60

80

100

2 4 6 8 10 12 14Sessions


Reversal

Cor

rect

resp

onse

s (

)

Wild-type (119899 = 16)Shn-2 KO (119899 = 5)

(d)



124=45597




7147= 3273 119875 = 00029)




6 Neural Plasticity

0

1

2

3

4

5

0 1 2 3 4 5 6

120572-C

aMKI

I HKO

mic

e (fo

ld ch

ange

)


119903 = 081 (119875 lt 00001)

(a)

Wild-type


Shn-2 KOWild-type

A130090K04RikWnk4

Ccnd1Fbxo7Unc5d

MGI1930803Spata13

LOC547362Nhlh1

Acvr1c

0 1 2 3 4 5

Ryr1Tspan18Pcdh21

Marcksl1

Capn3Calb1NpntDsp

Tdo2

0 05 1

0 1 2 3 4 5 6 7

0 05 1

120572-CaMKII HKO

1460043 at

(b)

Calbindin

Calretinin

Wild-type Shn-2 KO

Wild-type Shn-2 KO

500 120583m

250 120583m

(c)




Neural Plasticity 7











8 Neural Plasticity

0

1

2

3Re

lativ

e exp

ress

ion



lowastlowast



(a)

0

05

1

15

2Shn-2 KO mice

Rela

tive e

xpre

ssio

nShn-2 KO


Control


(b)

0

2

4

6

8


Rela

tive e

xpre

ssio

n

FLX

lowastlowast


Control


(c)

0

1

2

3

4

5

6


Rela

tive e

xpre

ssio

n

lowastlowast


PilocarpineControl


(d)




Neural Plasticity 9



Shn-2 KO[2]

SNAP-25KI [3]

CN KO[4 10 21]

FLXtreatment [5]












Molecularphenotypes


























LPS

treat

men

t (fo

ld ch

ange

)Pr

ion

infe

ctio

n (fo

ld ch

ange

)

Agi

ng (f

old

chan

ge)

Inju

ry (f

old

chan

ge)





01

1

10

0 1 2 301

1

10

100

0 1 2 3

01

1

10

100

0 1 2 30

1

2

3

4

0 1 2 3 4

(a)

(b)(f)(e)

(d)(c)

0

1

2

3

0 1 2

34 genes

42 genes 16 genes

8 genes

Schi

zoph

reni

a (fo

ld ch

ange

)


lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast


Fold change



158153CbIn4Tgm2Ma12

Sic14a1Mthfd2

GfapRgs4

D0H4S114Fbxo9Syn2


RP11ndash35N61Gng4




Serpina3nC1qbC1qc

C10orf10Rgs4

Ifitm2C1qaMyt1lTac1

CebpdFrzb

Ifitm1

Ifitm1

Tgfbr1Frzb

Ddit4
































































iDG






Decreased PPI


Model mice



Decreased PPI

Social withdrawal


Causes











Chronic SSRI


Chronic SSRI























10 Conclusion




Disclosure


Acknowledgment


References























































































































































































Neural Plasticity










Psychiatry Journal









Journal of


6 Neural Plasticity

0

1

2

3

4

5

0 1 2 3 4 5 6

120572-C

aMKI

I HKO

mic

e (fo

ld ch

ange

)


119903 = 081 (119875 lt 00001)

(a)

Wild-type


Shn-2 KOWild-type

A130090K04RikWnk4

Ccnd1Fbxo7Unc5d

MGI1930803Spata13

LOC547362Nhlh1

Acvr1c

0 1 2 3 4 5

Ryr1Tspan18Pcdh21

Marcksl1

Capn3Calb1NpntDsp

Tdo2

0 05 1

0 1 2 3 4 5 6 7

0 05 1

120572-CaMKII HKO

1460043 at

(b)

Calbindin

Calretinin

Wild-type Shn-2 KO

Wild-type Shn-2 KO

500 120583m

250 120583m

(c)




Neural Plasticity 7











8 Neural Plasticity

0

1

2

3Re

lativ

e exp

ress

ion



lowastlowast



(a)

0

05

1

15

2Shn-2 KO mice

Rela

tive e

xpre

ssio

nShn-2 KO


Control


(b)

0

2

4

6

8


Rela

tive e

xpre

ssio

n

FLX

lowastlowast


Control


(c)

0

1

2

3

4

5

6


Rela

tive e

xpre

ssio

n

lowastlowast


PilocarpineControl


(d)




Neural Plasticity 9



Shn-2 KO[2]

SNAP-25KI [3]

CN KO[4 10 21]

FLXtreatment [5]












Molecularphenotypes


























LPS

treat

men

t (fo

ld ch

ange

)Pr

ion

infe

ctio

n (fo

ld ch

ange

)

Agi

ng (f

old

chan

ge)

Inju

ry (f

old

chan

ge)





01

1

10

0 1 2 301

1

10

100

0 1 2 3

01

1

10

100

0 1 2 30

1

2

3

4

0 1 2 3 4

(a)

(b)(f)(e)

(d)(c)

0

1

2

3

0 1 2

34 genes

42 genes 16 genes

8 genes

Schi

zoph

reni

a (fo

ld ch

ange

)


lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast


Fold change



158153CbIn4Tgm2Ma12

Sic14a1Mthfd2

GfapRgs4

D0H4S114Fbxo9Syn2


RP11ndash35N61Gng4




Serpina3nC1qbC1qc

C10orf10Rgs4

Ifitm2C1qaMyt1lTac1

CebpdFrzb

Ifitm1

Ifitm1

Tgfbr1Frzb

Ddit4
































































iDG






Decreased PPI


Model mice



Decreased PPI

Social withdrawal


Causes











Chronic SSRI


Chronic SSRI























10 Conclusion




Disclosure


Acknowledgment


References























































































































































































Neural Plasticity










Psychiatry Journal









Journal of


Neural Plasticity 7











8 Neural Plasticity

0

1

2

3Re

lativ

e exp

ress

ion



lowastlowast



(a)

0

05

1

15

2Shn-2 KO mice

Rela

tive e

xpre

ssio

nShn-2 KO


Control


(b)

0

2

4

6

8


Rela

tive e

xpre

ssio

n

FLX

lowastlowast


Control


(c)

0

1

2

3

4

5

6


Rela

tive e

xpre

ssio

n

lowastlowast


PilocarpineControl


(d)




Neural Plasticity 9



Shn-2 KO[2]

SNAP-25KI [3]

CN KO[4 10 21]

FLXtreatment [5]












Molecularphenotypes


























LPS

treat

men

t (fo

ld ch

ange

)Pr

ion

infe

ctio

n (fo

ld ch

ange

)

Agi

ng (f

old

chan

ge)

Inju

ry (f

old

chan

ge)





01

1

10

0 1 2 301

1

10

100

0 1 2 3

01

1

10

100

0 1 2 30

1

2

3

4

0 1 2 3 4

(a)

(b)(f)(e)

(d)(c)

0

1

2

3

0 1 2

34 genes

42 genes 16 genes

8 genes

Schi

zoph

reni

a (fo

ld ch

ange

)


lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast


Fold change



158153CbIn4Tgm2Ma12

Sic14a1Mthfd2

GfapRgs4

D0H4S114Fbxo9Syn2


RP11ndash35N61Gng4




Serpina3nC1qbC1qc

C10orf10Rgs4

Ifitm2C1qaMyt1lTac1

CebpdFrzb

Ifitm1

Ifitm1

Tgfbr1Frzb

Ddit4
































































iDG






Decreased PPI


Model mice



Decreased PPI

Social withdrawal


Causes











Chronic SSRI


Chronic SSRI























10 Conclusion




Disclosure


Acknowledgment


References























































































































































































Neural Plasticity










Psychiatry Journal









Journal of


8 Neural Plasticity

0

1

2

3Re

lativ

e exp

ress

ion



lowastlowast



(a)

0

05

1

15

2Shn-2 KO mice

Rela

tive e

xpre

ssio

nShn-2 KO


Control


(b)

0

2

4

6

8


Rela

tive e

xpre

ssio

n

FLX

lowastlowast


Control


(c)

0

1

2

3

4

5

6


Rela

tive e

xpre

ssio

n

lowastlowast


PilocarpineControl


(d)




Neural Plasticity 9



Shn-2 KO[2]

SNAP-25KI [3]

CN KO[4 10 21]

FLXtreatment [5]












Molecularphenotypes


























LPS

treat

men

t (fo

ld ch

ange

)Pr

ion

infe

ctio

n (fo

ld ch

ange

)

Agi

ng (f

old

chan

ge)

Inju

ry (f

old

chan

ge)





01

1

10

0 1 2 301

1

10

100

0 1 2 3

01

1

10

100

0 1 2 30

1

2

3

4

0 1 2 3 4

(a)

(b)(f)(e)

(d)(c)

0

1

2

3

0 1 2

34 genes

42 genes 16 genes

8 genes

Schi

zoph

reni

a (fo

ld ch

ange

)


lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast


Fold change



158153CbIn4Tgm2Ma12

Sic14a1Mthfd2

GfapRgs4

D0H4S114Fbxo9Syn2


RP11ndash35N61Gng4




Serpina3nC1qbC1qc

C10orf10Rgs4

Ifitm2C1qaMyt1lTac1

CebpdFrzb

Ifitm1

Ifitm1

Tgfbr1Frzb

Ddit4
































































iDG






Decreased PPI


Model mice



Decreased PPI

Social withdrawal


Causes











Chronic SSRI


Chronic SSRI























10 Conclusion




Disclosure


Acknowledgment


References























































































































































































Neural Plasticity










Psychiatry Journal









Journal of


Neural Plasticity 9



Shn-2 KO[2]

SNAP-25KI [3]

CN KO[4 10 21]

FLXtreatment [5]












Molecularphenotypes


























LPS

treat

men

t (fo

ld ch

ange

)Pr

ion

infe

ctio

n (fo

ld ch

ange

)

Agi

ng (f

old

chan

ge)

Inju

ry (f

old

chan

ge)





01

1

10

0 1 2 301

1

10

100

0 1 2 3

01

1

10

100

0 1 2 30

1

2

3

4

0 1 2 3 4

(a)

(b)(f)(e)

(d)(c)

0

1

2

3

0 1 2

34 genes

42 genes 16 genes

8 genes

Schi

zoph

reni

a (fo

ld ch

ange

)


lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast


Fold change



158153CbIn4Tgm2Ma12

Sic14a1Mthfd2

GfapRgs4

D0H4S114Fbxo9Syn2


RP11ndash35N61Gng4




Serpina3nC1qbC1qc

C10orf10Rgs4

Ifitm2C1qaMyt1lTac1

CebpdFrzb

Ifitm1

Ifitm1

Tgfbr1Frzb

Ddit4
































































iDG






Decreased PPI


Model mice



Decreased PPI

Social withdrawal


Causes











Chronic SSRI


Chronic SSRI























10 Conclusion




Disclosure


Acknowledgment


References























































































































































































Neural Plasticity










Psychiatry Journal









Journal of














LPS

treat

men

t (fo

ld ch

ange

)Pr

ion

infe

ctio

n (fo

ld ch

ange

)

Agi

ng (f

old

chan

ge)

Inju

ry (f

old

chan

ge)





01

1

10

0 1 2 301

1

10

100

0 1 2 3

01

1

10

100

0 1 2 30

1

2

3

4

0 1 2 3 4

(a)

(b)(f)(e)

(d)(c)

0

1

2

3

0 1 2

34 genes

42 genes 16 genes

8 genes

Schi

zoph

reni

a (fo

ld ch

ange

)


lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast


Fold change



158153CbIn4Tgm2Ma12

Sic14a1Mthfd2

GfapRgs4

D0H4S114Fbxo9Syn2


RP11ndash35N61Gng4




Serpina3nC1qbC1qc

C10orf10Rgs4

Ifitm2C1qaMyt1lTac1

CebpdFrzb

Ifitm1

Ifitm1

Tgfbr1Frzb

Ddit4
































































iDG






Decreased PPI


Model mice



Decreased PPI

Social withdrawal


Causes











Chronic SSRI


Chronic SSRI























10 Conclusion




Disclosure


Acknowledgment


References























































































































































































Neural Plasticity










Psychiatry Journal









Journal of































































iDG






Decreased PPI


Model mice



Decreased PPI

Social withdrawal


Causes











Chronic SSRI


Chronic SSRI























10 Conclusion




Disclosure


Acknowledgment


References























































































































































































Neural Plasticity










Psychiatry Journal









Journal of
















10 Conclusion




Disclosure


Acknowledgment


References























































































































































































Neural Plasticity










Psychiatry Journal









Journal of


















































































































































































Neural Plasticity










Psychiatry Journal









Journal of


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