Chapter 10: Molecular Genetic Mechanisms for Long-Term Information Storage at the Cellular Level
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Transcript of Chapter 10: Molecular Genetic Mechanisms for Long-Term Information Storage at the Cellular Level
Chapter 10:Molecular Genetic Mechanisms
for Long-Term Information Storage at the Cellular Level
From Mechanisms of Memory, second editionBy J. David Sweatt, Ph.D.
Chapter 10: Chromatin Remodeling in Memory Formation
Figure 1
Protein Synthesis Dependence of L-LTP
Figure 2
CREB Binding Protein (CBP)
cAMP Response Element5’-TGACGTCA-3’
TATA Sequence
CREB CREB
Basal Transcription Factor IID (TFIID)
Complex
ser 133 ser 133
RNA Helicase A
RNAPolymerase II
Histone
pKAF
acetylation
TargetGene
PO4 PO4
CREB/CRE Gene Regulation System
Figure 3
Crystal Structure of CREB Bound to the CRE
Fig
ure
4Activity-Dependent Regulation of Gene Expression in
Neurons
Figure 5
BA Long-Term Potentiation
Impaired Long-term Synaptic Plasticity in C-Rel- /- Mice
Fig
ure
6
CRE SRE zif268
C/EBP krox20
AMPARHOMERBDNFNT-3
MKP-1SSAT
Arc
CBP/CREB
CaMKIV + ERK
Elk-1
RSK2
Transcriptional Regulation Pathways Controlling Expression of Synaptic Plasticity-Associated Genes
Figure 7
Activity-Dependent ARC Expression and Dendritic Localization
Figure 8
Hypothetical Mechanisms and Activity-Dependent Changes in Synaptic Structure
Figure 9
Presynaptic
Postsynaptic
Integrins
Integrins
Ca++Ca++
actin
Pax
illin
FAK (Focal Adhesion Kinase)
grb2/sos cas/crk src
ERK JNK
α αββrho rac
Dynamiccytoskeletalregulation
Cadherins
Catenins
?
DMPK
MyosinPhosphatase
CytoskeletalMyosin II
-
-
α-actinintalin
vincu
lin α-actinin
Signaling Mechanisms Utilized by Integrins and Cadherins
Figure 10
Memory and the Cellular Level
Figure 11
BA
Methylation of Cytosine Side-Chains in DNA
Figure 12
“CpG Island” in the BDNF Gene
Figure 13
MBD
TRDMeDNABINDINGPROTEIN
Adapter Protein
HDAC1
HDAC2
AcAc
DNA Methylation-Dependent Gene Silencing
Figure 14
Homology Model of MBD of MECP2 Interacting with CpG within DNA Duplex
Figure 15
Nucleosome Interaction with DNA
Figure 16
The Histone Code
HistoneAcetyltransferase
(HAT)
HistoneDeacetylase
(HDAC)
Figure 17
Bidirectional Regulation of Histone Acetylation by HAT’s and HDAC’s
Figure 18
Epigenetics in Contextual Fear Memory --- Histone Code
Figure 19
Neurogenesis in the Adult Human Hippocampus
TABLE I – THE CASE FOR GENE EXPRESSION IN L-LTP
EXPERIMENT TYPE
FINDING REFERENCES
Block Block of L-LTP with protein synthesis inhibitors (76)
Block of L-LTP with RNA synthesis inhibitors (1, 2, 77)
Loss of L-LTP with CREB KOs (3-5)
Block of L-LTP with Arc antisense (13)
Loss of L-LTP with CaMKIV KO (7, 8, 78)
Loss of L-LTP with zif268 KO (6)
Loss of L-LTP with c-rel KO (21)
EXPERIMENT TYPE
FINDING REFERENCES
Measure Increased zif268 / krox24 mRNA (40)
Increased krox20 (44)
Increased expression of fos, jun IEG mRNAs (40, 42, 43)
Increased CREB phosphorylation (24, 34, 35)
Increased CRE read-out (12, 79)
Increased elk-1 phosphorylation (35)
Increased Arc/Arg3.1 mRNA expression (13, 54, 59)
Increased AMPA receptor protein (51)
Increased BDNF message (46, 80)
Increased tissue Plasminogen Activator message (47)
Increased C/EBP beta (in long-term memory) (45)
Increased HOMER (11, 53, 72)
Increased MAP Kinase Phosphatase-1 (35, 50)
Increased SSAT message (49)
Increased MAP2 message (81)
TABLE I – THE CASE FOR GENE EXPRESSION IN L-LTPCONTINUED
EXPERIMENT TYPE
FINDING REFERENCES
MimicConstitutively active CREB augments L-LTP induction (14)
TABLE I – THE CASE FOR GENE EXPRESSION IN L-LTPCONTINUED
DISEASE GENE FUNCTION EPIGENETIC EFFECT
Rubinstein-Taybi Syndrome
CBP Histoneacetyltransferase
↑ histone acetylation
Rett Syndrome MECP2 Binds to CpG dinucleotides and recruits HDACs
↓ histone acetylation
Fragile X mental retardation
FMR1 and FMR2* Expansion of CGG or CCG repeats results in aberrant DNA methylation around FMR1 and FMR2 genes
↑ DNA methylation↑ histone acetylation
Alzheimer’s disease APP APP intracellular domain acts as a Notch-like transcription factor; associated with the HAT TIP60
↓ histone acetylation
Schizophrenia reelin An extracellular matrix protein, involved in synapse development
↑ DNA methylationaround the reelin gene
*Trinucleotide expansions in FMR1 and FMR2. APP, amyloid precursor protein; CBP, cyclic-AMP response-element-binding protein; FMR, fragile X mental retardation; HAT, histone acetyltransferases; HDAC, histone deacetylase; MECP2, methyl CpG-binding protein 2; TIP60, HIV-1 Tat interactive protein, 60kDa.
TABLE II – EPIGENETICS IN HUMAN COGNITIVEDISORDERS
Blue Box 1
Neural Development and Differentiation
Mother’s Day --- Everyday of Your Life
Blue Box 2