DECONSTRUCTING PSYCHOSIS

Francine M. Benes, M.D., Ph.D.

Program in Structural and Molecular Neuroscience,McLean Hospital

Program in Neuroscience and Department of PsychiatryHarvard Medical School

TEL: 617-855-2401FAX: 617-855-3199

E-mail: fbenes@mclean.harvard.edu

SUSCEPTIBILITYSUSCEPTIBILITY

Inherited GenesInherited Genes

Environmentally-Regulated GenesEnvironmentally-Regulated Genes

Two Factor Modeling in Defining Cellular Endophenotypes of SZ and BD

Endophenotype

Rat

Inhibitory GABA Interneuron

Pyramidal Cell

SCHIZOPHRENIANORMAL

Glutamatergic Fiber: Cortico-Cortical Association Fiber?

Abnormal Neural Circuitry in Layer II of Anterior Cingulate Cortexin Schizophrenia and Bipolar Disorder

Circa 1992

NMDA Down-Regulation??

NMDA Receptors

Woo, Walsh and Benes. Arch. Gen. Psychiat. (2004)

Laminar Changes in Laminar Changes in Anterior Cingulate CortexAnterior Cingulate Cortex of Schizophrenics and Bipolarsof Schizophrenics and Bipolars

Pyramidal cellsPyramidal cells

Nonpyramidal Somata (3)Nonpyramidal Somata (3)

GABAGABAA A RBARBA

GADGAD6565 Term. (CPZ+)* Term. (CPZ+)*

GluRGluR5,6,75,6,7-IR Neurons-IR Neurons

TH-IR VaricositiesTH-IR Varicosities****

Klennow Klennow + Nuclei***+ Nuclei***

Vertical Glut-IR Axons (3)Vertical Glut-IR Axons (3)

NRNR2A2A + GABA Cells + GABA Cells

GADGAD6767 + Cells + Cells

Klenow + Non-GABA CellsKlenow + Non-GABA Cells

NPs PNs

II II II III III V V VI VI

Area Dentata CA3/2 CA1

??

SchizophrenicSchizophrenic

Granule Layer

Area Dentata CA3/2 CA1

SM

SR

SP

SO

Perforant Path

SubiculumAmygdalaEntorhinal Cx

AlveusSchaffer Collaterals

Mossy Fibers

Feed Forward ExcitationFeed Forward Excitation

Entorhinal Cx

Septal NucleiHypothalamus

Normal ControlNormal Control

Influence of Amygdala on Hippocampal Integration in SZ Influence of Amygdala on Hippocampal Integration in SZ

AmygdalaAmygdala

AmygdalaAmygdala

BLn of Amygdala

BLn = Basolateral Nucleus

AnterogradelyTraced BLn Fibers

CA2/CA3CA2/CA3

Rodent Modeling for Neural Circuitry Changes in Limbic Lobe of SZs and BDsDirect Connections of Basolateral Amygdala (BLn) with ACCx-II and HIPP CA3/2 in Relation to SZ and BD

Berretta, Munno and Benes, J. Comp. Neurol., 1999

Picrotoxin Experiments

GABA Currents (GABA Currents (IPSCsIPSCs) in Hippocampus of Picrotoxin-Treated Rats) in Hippocampus of Picrotoxin-Treated Rats

Stimulation intensity (normalized)

0 1 2 3 4 5 6

IPS

C a

mp

litud

e (p

A)

0

100

200

300

400

Stimulation intensity (normalized)

0 1 2 3 4 5 6

IPS

C a

mp

litud

e (p

A)

0

100

200

300

400 picrosaline

50pA25ms

CA3CA3

CA1CA1

Gisabella, Bolshakov and Benes PNAS (2005) Gisabella, Bolshakov and Benes PNAS (2005)

Granulecell

SM

SRSP

Areadentata

CA3/2 CA1

SO

mossyfibers

Pyramidalcell

GABAinterneuron

Stim

Rec

+

_

+-

+

Pyramidalcell

SRSR

SPSP

SOSO

Schaffer Collateral

Regulation of Apoptosis in Schizophrenia and Bipolar Disorder

Voltage-Gated Ca+2 Ch 1D

Death LigandsVoltage-Gated Ca+2 Ch 1D

Death Ligands

Decreased Expression

Increased ExpressionBenes, Matzilevich, Walsh and Lim Molecular Psychiatry (2005)

Anti-Oxidant Genes in Normal Controls versus Bipolars and Schizophrenics

Description GenBank Fold Change P-Value

Bipolar Disorder

lactoperoxidase U39573 1.09 0.064

heme oxygenease 1 Z82244 1.14 0.131

superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) X02317 -1.21 0.081

catalase AL035079 -1.17 0.124

glutathione peroxidase 2 (gastrointestinal) X53463 1.11 0.041

glutathione peroxidase 4 (phospholipid hydroperoxidase) X71973 -1.23 0.014

glutathione peroxidase 1 X13710 -1.14 0.134

glyoxalase 1 NM006708 -1.32 0.014

microsomal glutathione S-transferase 3 AF026977 -1.39 0.002

hydroxyacyl glutathione hydrolase X90999 -1.36 0.028

glutathione S-transferase A4 AF025887 -1.24 0.046

glutathione S-transferase M3 (brain) AF043105 -1.19 0.198

esterase D/formylglutathione hydrolase AF112219 -1.31 0.044

glutathione synthetase U34683 -1.23 0.015

glutathione S-transferase A2 M16594 1.16 0.045

glutathione S-transferase M5 L02321 1.14 0.032

glutathione-S-transferase like; glutathione transferase omega U90313 -1.25 0.021

C-terminal PDZ domain ligand of neuronal nitric oxide synthase AB007933 -1.12 0.090

Human neuronal nitric oxide synthase (NOS1) gene, exon 29, and complete cds U17326 1.17 0.030

Human inducible nitric oxide synthase gene, promoter and exon 1 D29675 1.13 0.083

nitric oxide synthase 3 (endothelial cell) M93718 1.23 0.059

Schizophrenia

glutathione synthetase U34683 -1.18 0.050

↓ ↓ GADGAD6767 + + ↓↓ApoptosisApoptosis ↓↓ NR2A NR2A ↓ ↓ L-TypeL-Type CalciumCalcium →→ Schizophrenia Schizophrenia

Channel Channel 1D - Anti-Oxidation - Anti-Oxidation

↓↓ GADGAD6767 + + ↑ ↑ ApoptosisApoptosis ↓↓ NR2A NR2A ↑ ↑ L-Type Ca Ch 1D L-Type Ca Ch 1D →→ Bipolar DisorderBipolar Disorder

↓↓ Anti-OxidationAnti-Oxidation

Environmental + Susceptibility Environmental + Susceptibility →→ EndophenotypeEndophenotype Genes Genes GenesGenes

Pre- and/or PostnatalPre- and/or PostnatalStress Stress

Turned-On/OffTurned-On/OffIn AdolescenceIn Adolescence

TWO FACTOR MODEL OF PSYCHOTIC DISORDERSTWO FACTOR MODEL OF PSYCHOTIC DISORDERS