Genetic models for schizophrenia research

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Genetic modelsfor schizophreniaresearch
Jared W. Young, Ph.D.
Department of Psychiatry, University of
California, San Diegojaredyoung_at_ucsd.edu
JWY
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Schizophrenia Genetic contribution

• Horrobin postulated that the genes that separates
  us from chimpanzees, contain those that lead to
  schizophrenia
• True that schizophrenia has a genetic basis

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Genes linked to schizophrenia

• Its complicated

http//www.schizophreniaforum.org/res/sczgene/TopR
esults.asp for detailed information
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SZgene research tool
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Szgene Top 20
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Rat models

• All genetic associations listed were assessed in
  schizophrenia populations
• Limited rat genetic models used in psychiatry
• Strain differences
• WKHA/WKY (activity), RLA/RHA (fear)
• BRAT/LE (PPI)
• Selective breeding
• SHR/LEW (hypertensive), WKY/HEP (ethanol)
• Genetic mapping of Quantitative Trait Loci

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Mouse ModelsArguello and Gogos 2010

• Reviews recent behavioral studies in mouse models
  of schizophrenia susceptibility genes
• Genes chosen based on the top 30 susceptibility
  genes
• Cognitive testing in models where applicable to
  CNTRICS
• The review ultimately highlights
• There are genetic models available
• The paradigms they have been tested in have
  limited validity to the cognitive construct laid
  out by CNTRICS
• Tasks assaying these constructs remain limited
• Researchers will continue to shoe-horn a task
  into a domain
• Mouse Genome Project allows easier manipulation
  of genes for specific schizophrenia relevance

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Realistic genetic influence

• Heterogeneity of schizophrenia means individual
  gene effects on the clinical syndrome are small
• Genes are more likely to influence intermediate
  phenotypes which are theoretically closer to the
  gene action
• Thus a single genetic model should not be
  expected to reproduce the entire clinical
  syndrome
• Each model may prove fruitful for specific
  aspects of the disease
• (Cannon Keller, 2006, the water shed model)

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Investigating intermediate phenotypes-a7 nAChR
mutants

• Strong link between the a7 nicotinic
  acetylcholine receptor (nAChR) schizophrenia
  (Freedman et al, 1997)
• Implication of CHRFAM7A/CHRNA7 locus in episodic
  memory deficits in schizophrenia (Dempster et al,
  2006)
• Allelic variations occur (Freedman et al, 2006)
• No mouse models of these alleles exist as yet
• Knockout mice do exist (Orr-Urtreger et al, 1997)
• Can be used to examine impact on behavior

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Phenotype of a7 nAChR mutant mice

• First described by Paylor et al, (1998)
• Normal in exploration (activity rearing)
  altered ethanol effects? Bowers 2006
• anxiety (light/dark box)
• PPI (varying prepulse intensities unaffected
  by ethanol, Bowers 2006)
• startle amplitude rotarod performance
• Pavlovian fear conditioning
• spatial learning and memory (water maze)
• Exhibit normal nicotine-induced seizures
  (Franceschini et al, 2002)
• Impaired attention (5-CSR task Young et al,
  2004 Hoyle et al, 2006 Young et al, 2007 gene
  dose effect)
• Impaired DMTP (water maze, 20min Fernandes et
  al, 2006)
• Operant learning? (Keller et al, 2005 Young et
  al, 2004 2007)

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Gene dosage effects

• Heterozygotes (HT) are rarely tested in behavior
• Can be useful however as HT often ? expression

• Impaired attention in a7 KO mice
• Measured in the 5-CSR task
• (Young et al, 2004 Hoyle et al, 2006)
• Measured as ? omissions
• When HT mice included
• Gene dosage effect
• Effect of polymorphism?

(Young et al 2007)
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Selectivity of a7 nAChR to attentional mechanisms?

• a7 nAChR KO mice exhibit other cognitive
  deficiencies (OST, Young et al, 2007)
  attentional link

Dissecting the watershed model One step at a time
Sustained Attention (omissions)
Neuron Mech
a7
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NIMH drive for mice with human alleles

• NIMH issued a RFA in 2007 RFA-MH-08-050
• Mouse Models Containing Human Alleles a R21/R33
• Since reissued in 2008 as PAR-08-158
• Funded 5 of 11 with links to schizophrenia
• GAD67-ERB4
• COMT VARIANTS IN SENSORIMOTOR GATING
• G72/G30 TRANSGENIC MICE
• DISC1-BOYMAW FUSION TRANSCRIPTS
• DRD2 SER311CYS POLYMORPHISM

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Understanding Gene X Drug interactions

• Personalized medicine
• Antipsychotic responses in CATIE (van den Oord et
  al, 2009)
• Weight gain following olanzapine (Muller and
  Kennedy, 2006)
• COMT Val/Met alleles and risperidone response
  (Gupta et al, 2009)
• PPI and COMT Val/Met alleles in schizophrenia
  (Quednow et al, 2009)
• Cognitive response to clozapine in schizophrenia
  (Woodward et al, 2007)

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Catechol-O-methyltransferase Val158Met
polymorphism

• Single nucleotide polymorphism of COMT
• Missense mutation of codon 158 Val to Met
• Unique to humans
• Met allele may confer improved executive
  functioning and working memory
• Val allele may confer sensitivity to
  environmental insults such as marijuana use
  (Caspi et al, 2005)
• Tolcapone-induced improvements in PPI and
  executive function only in Val groups (Giakoumaki
  et al, 2008)

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Understanding COMT allele X Drug

• COMT KO mice (Babovic et al, 2007)
• Over-expression of 22q11.2 segment including
  TXNRD2, COMT and ARVCF (Suzuki et al, 2009 Stark
  et al 2009)
• Provides insight into COMT mechanisms
• As before with a7 nAChR KO mice
• Limited use in understanding allelic
  contributions drug effects
• cognitive functioning
• psychiatric disorders

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Val158Met mice

• Mouse Models Containing Human Alleles R21/R33
• NIMH grant PAR-08-158
• COMT VARIANTS IN SENSORIMOTOR GATING

Risbrough Zhou
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Planned behavioral studies

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

Dissecting the watershed model Two steps forward
Behaviors
DRUG
PFC dopamine clearance
Met
Environment Impact
Val
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One gene at a time
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Conclusion for Genetic Models

• Positives
• ? in number sophistication for the human allele
• Are developmental in nature
• Allow for
• Genetic environmental models
• Drug X gene interaction studies

• Negatives
• Cognitive tasks not as well developed
• Lesion and pharmacological validation required

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Thanks for listening
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Thanks
NARSAD Young Investigator Award 2008-2010
Mark A Geyer Vickie Risbrough Susan
Powell Jessica Meves Richard Pete Sharp
Mahalah Buell Tammy Zhou Christine
Scott Sorana Caldwell
Pala Grant Awards
Dilip V. Jeste
David Braff Greg Light Anthony Rissling
Lisa Eyler Greg Asgaard
R21 funding to validate the 5C-CPT