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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
[email protected]@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