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Genetic modelsGenetic modelsfor schizophreniafor schizophrenia

researchresearch

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Jared W. Young, Ph.D.Jared W. Young, Ph.D.

Department of Psychiatry, Department of Psychiatry, University of California, San DiegoUniversity of California, San Diego

jaredyoung@ucsd.edujaredyoung@ucsd.edu

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Schizophrenia: Schizophrenia: Genetic contributionGenetic contribution

Horrobin postulated that the genes that Horrobin postulated that the genes that separates us from chimpanzees, contain separates us from chimpanzees, contain those that lead to schizophreniathose that lead to schizophrenia

True that schizophrenia has a genetic basis:True that schizophrenia has a genetic basis:

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Genes linked to Genes linked to schizophreniaschizophrenia

It’s complicated…It’s complicated…

http://www.schizophreniaforum.org/res/sczgene/http://www.schizophreniaforum.org/res/sczgene/TopResults.asp for detailed informationTopResults.asp for detailed information

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SZgene – research SZgene – research tooltool

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Szgene – Top 20Szgene – Top 20

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Rat modelsRat models

All genetic associations listed were All genetic associations listed were assessed in schizophrenia populationsassessed in schizophrenia populations

Limited rat genetic models used in Limited rat genetic models used in psychiatrypsychiatry

Strain differencesStrain differences WKHA/WKY (activity), RLA/RHA (fear)WKHA/WKY (activity), RLA/RHA (fear) BRAT/LE (PPI)BRAT/LE (PPI)

Selective breeding:Selective breeding: SHR/LEW (hypertensive), WKY/HEP (ethanol)SHR/LEW (hypertensive), WKY/HEP (ethanol)

Genetic mapping of Quantitative Trait Genetic mapping of Quantitative Trait LociLoci

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Mouse Models:Mouse Models:Arguello and Gogos Arguello and Gogos

20102010 Reviews recent behavioral studies in mouse models of Reviews recent behavioral studies in mouse models of

schizophrenia susceptibility genesschizophrenia susceptibility genes Genes chosen based on the top 30 susceptibility genesGenes chosen based on the top 30 susceptibility genes Cognitive testing in models where applicable to Cognitive testing in models where applicable to

CNTRICSCNTRICS The review ultimately highlights:The review ultimately highlights:

There are genetic models availableThere are genetic models available The paradigms they have been tested in have limited validity The paradigms they have been tested in have limited validity

to the cognitive construct laid out by CNTRICSto the cognitive construct laid out by CNTRICS Tasks assaying these constructs remain limitedTasks assaying these constructs remain limited Researchers will continue to ‘shoe-horn’ a task into a domainResearchers will continue to ‘shoe-horn’ a task into a domain

Mouse Genome Project allows easier manipulation of Mouse Genome Project allows easier manipulation of genes for specific schizophrenia relevancegenes for specific schizophrenia relevance

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Realistic genetic Realistic genetic influenceinfluence

Heterogeneity of schizophrenia means individual Heterogeneity of schizophrenia means individual gene effects on the clinical syndrome are smallgene effects on the clinical syndrome are small

Genes are more likely to influence intermediate Genes are more likely to influence intermediate phenotypes which are theoretically closer to the phenotypes which are theoretically closer to the gene actiongene action

Thus a single genetic model should not be expected Thus a single genetic model should not be expected to reproduce the entire clinical syndrometo reproduce the entire clinical syndrome

Each model may prove fruitful for specific aspects Each model may prove fruitful for specific aspects of the diseaseof the disease

(Cannon & Keller, 2006, the water shed model)(Cannon & Keller, 2006, the water shed model)

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Investigating Investigating intermediate intermediate

phenotypes-phenotypes-αα7 nAChR 7 nAChR mutantsmutants

Strong link between the Strong link between the αα7 nicotinic 7 nicotinic acetylcholine receptor acetylcholine receptor (nAChR) (nAChR) & & schizophrenia schizophrenia (Freedman et al, 1997)(Freedman et al, 1997)

Implication of CHRFAM7A/CHRNA7 locus Implication of CHRFAM7A/CHRNA7 locus in episodic memory deficits in in episodic memory deficits in schizophrenia schizophrenia (Dempster et al, 2006)(Dempster et al, 2006)

Allelic variations occur Allelic variations occur (Freedman et al, 2006)(Freedman et al, 2006)

No mouse models of these alleles exist as No mouse models of these alleles exist as yetyet

Knockout mice do exist Knockout mice do exist (Orr-Urtreger et al, 1997)(Orr-Urtreger et al, 1997) Can be used to examine impact on behaviorCan be used to examine impact on behavior

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Phenotype of Phenotype of αα7 7 nAChR mutant micenAChR mutant mice

First described by Paylor et al, (1998)First described by Paylor et al, (1998) Normal in Normal in exploration (activity & rearing) [altered ethanol effects? exploration (activity & rearing) [altered ethanol effects?

Bowers 2006]Bowers 2006]

anxiety (light/dark box)anxiety (light/dark box)

PPI (varying prepulse intensities [unaffected by ethanol, PPI (varying prepulse intensities [unaffected by ethanol, Bowers 2006])Bowers 2006])

startle amplitude + rotarod performancestartle amplitude + rotarod performance

Pavlovian fear conditioningPavlovian fear conditioning

spatial learning and memory (water maze)spatial learning and memory (water maze)

Exhibit normal nicotine-induced seizures Exhibit normal nicotine-induced seizures (Franceschini et al, (Franceschini et al, 2002)2002)

Impaired attention (5-CSR task; Impaired attention (5-CSR task; Young et al, 2004; Hoyle et Young et al, 2004; Hoyle et al, 2006; Young et al, 2007 [gene dose effect]al, 2006; Young et al, 2007 [gene dose effect]))

Impaired DMTP (water maze, Impaired DMTP (water maze, 20min20min; ; Fernandes et al, 2006)Fernandes et al, 2006) Operant learning? Operant learning? (Keller et al, 2005: Young et al, 2004; 2007)(Keller et al, 2005: Young et al, 2004; 2007)

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Gene dosage effectsGene dosage effects

Heterozygotes (HT) are rarely tested in behaviorHeterozygotes (HT) are rarely tested in behavior Can be useful however as HT often = ↓ expressionCan be useful however as HT often = ↓ expression

WT HT KO

% O

mis

sio

ns

0

7

14

21

28

35

Impaired attention in Impaired attention in αα7 7 KO miceKO mice

Measured in the 5-CSR Measured in the 5-CSR tasktask(Young et al, 2004; Hoyle et (Young et al, 2004; Hoyle et al, 2006)al, 2006)

Measured as ↑ % Measured as ↑ % omissionsomissions

When HT mice included:When HT mice included: Gene dosage effectGene dosage effect Effect of polymorphism?Effect of polymorphism?

(Young et al (Young et al 2007)2007)

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Selectivity of Selectivity of αα7 7 nAChR to attentional nAChR to attentional

mechanisms?mechanisms? αα7 nAChR KO mice exhibit other cognitive 7 nAChR KO mice exhibit other cognitive

deficiencies deficiencies (OST, Young et al, 2007) (OST, Young et al, 2007) – attentional – attentional linklink

NeurNeuronon

MechMech

αα77

SustaineSustained d AttentioAttentionn(omissio(omissions)ns)

Dissecting the watershed modelDissecting the watershed modelOne step at a timeOne step at a time

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NIMH drive for mice NIMH drive for mice with human alleleswith human alleles

NIMH issued a RFA in 2007 RFA-MH-08-NIMH issued a RFA in 2007 RFA-MH-08-050050

““Mouse Models Containing Human Alleles” a Mouse Models Containing Human Alleles” a R21/R33R21/R33

Since reissued in 2008 as PAR-08-158Since reissued in 2008 as PAR-08-158 Funded 5 of 11 with links to schizophrenia: Funded 5 of 11 with links to schizophrenia:

GAD67-ERB4GAD67-ERB4 COMT VARIANTS IN SENSORIMOTOR GATINGCOMT VARIANTS IN SENSORIMOTOR GATING G72/G30 TRANSGENIC MICEG72/G30 TRANSGENIC MICE DISC1-BOYMAW FUSION TRANSCRIPTSDISC1-BOYMAW FUSION TRANSCRIPTS DRD2 SER311CYS POLYMORPHISMDRD2 SER311CYS POLYMORPHISM

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Understanding Gene Understanding Gene X Drug interactionsX Drug interactions

Personalized medicinePersonalized medicine Antipsychotic responses in CATIE Antipsychotic responses in CATIE (van (van

den Oord et al, 2009)den Oord et al, 2009) Weight gain following olanzapine Weight gain following olanzapine (Muller (Muller

and Kennedy, 2006)and Kennedy, 2006) COMT Val/Met alleles and risperidone COMT Val/Met alleles and risperidone

response response (Gupta et al, 2009)(Gupta et al, 2009) PPI and COMT Val/Met alleles in PPI and COMT Val/Met alleles in

schizophrenia schizophrenia (Quednow et al, 2009)(Quednow et al, 2009) Cognitive response to clozapine in Cognitive response to clozapine in

schizophrenia schizophrenia (Woodward et al, 2007)(Woodward et al, 2007)

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Catechol-O-Catechol-O-methyltransferase methyltransferase

Val158Met Val158Met polymorphismpolymorphism

Single nucleotide polymorphism of COMTSingle nucleotide polymorphism of COMT Missense mutation of codon 158 Val to MetMissense mutation of codon 158 Val to Met Unique to humansUnique to humans Met allele may confer improved executive Met allele may confer improved executive

functioning and working memoryfunctioning and working memory Val allele may confer sensitivity to Val allele may confer sensitivity to

environmental insults such as marijuana environmental insults such as marijuana use use (Caspi et al, 2005)(Caspi et al, 2005)

Tolcapone-induced improvements in PPI Tolcapone-induced improvements in PPI and executive function only in Val groups and executive function only in Val groups (Giakoumaki et al, 2008)(Giakoumaki et al, 2008)

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Understanding Understanding COMT allele X DrugCOMT allele X Drug

COMT KO mice COMT KO mice (Babovic et al, 2007)(Babovic et al, 2007) Over-expression of 22q11.2 segment Over-expression of 22q11.2 segment

including TXNRD2, COMT and ARVCF including TXNRD2, COMT and ARVCF (Suzuki et al, 2009; Stark et al 2009)(Suzuki et al, 2009; Stark et al 2009)

Provides insight into COMT Provides insight into COMT mechanismsmechanisms As before with As before with αα7 nAChR KO mice7 nAChR KO mice

Limited use in understanding allelic Limited use in understanding allelic contributions: contributions: drug effectsdrug effects

cognitive functioningcognitive functioningpsychiatric disorderspsychiatric disorders

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Val158Met miceVal158Met mice

““Mouse Models Containing Human Mouse Models Containing Human Alleles”: R21/R33Alleles”: R21/R33

NIMH grant PAR-08-158NIMH grant PAR-08-158COMT VARIANTS IN SENSORIMOTOR COMT VARIANTS IN SENSORIMOTOR

GATINGGATING

Risbrough & ZhouRisbrough & Zhou

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Planned behavioral Planned behavioral studiesstudies

Assessment of PPI, 5-CSR , and odor span taskAssessment of PPI, 5-CSR , and odor span task Sensitivity to environmental insultsSensitivity to environmental insults

PFC PFC dopamidopami

ne ne clearanclearan

cece

VValal

BehavioBehaviorsrs

Dissecting the watershed modelDissecting the watershed modelTwo steps forwardTwo steps forward

MeMett EnvironmEnvironm

ententImpactImpact

DRUGDRUG

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One gene at a timeOne gene at a time

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Conclusion for Conclusion for Genetic ModelsGenetic Models

Positives:Positives: ↑ ↑ in number & sophistication for the in number & sophistication for the

human allelehuman allele Are developmental in natureAre developmental in nature Allow for: Allow for:

Genetic + environmental modelsGenetic + environmental models

Drug X gene interaction studiesDrug X gene interaction studies Negatives:Negatives: Cognitive tasks not as well developedCognitive tasks not as well developed

Lesion and pharmacological validation Lesion and pharmacological validation requiredrequired

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Thanks for Thanks for listeninglistening

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ThanksThanks

Mark A GeyerMark A GeyerVickie Risbrough Vickie Risbrough

Susan PowellSusan PowellJessica MevesJessica MevesRichard ‘Pete’ Richard ‘Pete’

Sharp Sharp Mahalah Buell Mahalah Buell Tammy Zhou Tammy Zhou

Christine ScottChristine ScottSorana CaldwellSorana Caldwell

Pala Grant AwardsPala Grant Awards

NARSAD Young NARSAD Young Investigator AwardInvestigator Award

2008-20102008-2010

Dilip V. JesteDilip V. JesteDavid David

BraffBraffGreg Greg

LightLightAnthony Anthony

RisslingRissling

Lisa Lisa EylerEyler

Greg Greg AsgaardAsgaardR21 funding to R21 funding to

validate the 5C-validate the 5C-CPTCPT