Genetic models for schizophrenia research

1. Genetic modelsfor schizophreniaresearch Jared W. Young, Ph.D. Department of Psychiatry, University of California, San Diegojaredyoung@ucsd.edu JWY

2. 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:

4. Genes linked to schizophrenia http://www.schizophreniaforum.org/res/sczgene/TopResults.asp for detailed information It’s complicated…

5. SZgene – research tool

6. Szgene – Top 20

7. 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

8. Mouse Models:Arguello 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

9. 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)

11. Investigating intermediate phenotypes-α7 nAChR mutants • Strong link between the α7 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

12. Phenotype of α7 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)

13. Gene dosage effects • Impaired attention in α7 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? Heterozygotes (HT) are rarely tested in behavior Can be useful however as HT often = ↓ expression (Young et al 2007)

14. Selectivity of α7 nAChR to attentional mechanisms? Dissecting the watershed model One step at a time Sustained Attention (omissions) Neuron Mech α7 α7 nAChR KO mice exhibit other cognitive deficiencies (OST, Young et al, 2007) – attentional link

15. 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

16. 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)

17. 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)

18. 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 α7 nAChR KO mice • Limited use in understanding allelic contributions: drug effects cognitive functioning psychiatric disorders

19. Val158Met mice Risbrough & Zhou “Mouse Models Containing Human Alleles”: R21/R33 NIMH grant PAR-08-158 COMT VARIANTS IN SENSORIMOTOR GATING

20. Planned behavioral studies Dissecting the watershed model Two steps forward Behaviors DRUG PFC dopamine clearance Met Environment Impact Val Assessment of PPI, 5-CSR , and odor span task Sensitivity to environmental insults

21. One gene at a time

22. 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

23. Thanks for listening

24. 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