Transcript Jared Young: Genetic models for schizophrenia research

Genetic models
for schizophrenia
research
Jared W. Young, Ph.D.
Department of Psychiatry,
University of California, San Diego
[email protected]
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Schizophrenia:
Genetic contribution
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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
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It’s complicated…
http://www.schizophreniaforum.org/res/sczgene/TopResults.asp
for detailed information
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SZgene – research tool
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Szgene – Top 20
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Rat models
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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)
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Selective breeding:
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SHR/LEW (hypertensive), WKY/HEP (ethanol)
Genetic mapping of Quantitative Trait Loci
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Mouse Models:
Arguello and Gogos 2010
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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:
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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-α7 nAChR mutants
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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)
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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)
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Can be used to examine impact on behavior
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Phenotype of α7 nAChR
mutant mice
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First described by Paylor et al, (1998)
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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
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Heterozygotes (HT) are rarely tested in behavior
Can be useful however as HT often = ↓ expression
35
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Impaired attention in α7 KO mice
Measured in the 5-CSR task
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(Young et al, 2004; Hoyle et al, 2006)
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Measured as ↑ % omissions
When HT mice included:
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Gene dosage effect
Effect of polymorphism?
% Omissions
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14
7
0
WT
HT
KO
(Young et al 2007)
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Selectivity of α7 nAChR to
attentional mechanisms?
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α7 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
α7
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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:
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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
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Personalized medicine
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Antipsychotic responses in CATIE (van den Oord et
al, 2009)
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Weight gain following olanzapine (Muller and
Kennedy, 2006)
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COMT Val/Met alleles and risperidone response
(Gupta et al, 2009)
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PPI and COMT Val/Met alleles in schizophrenia
(Quednow et al, 2009)
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Cognitive response to clozapine in schizophrenia
(Woodward et al, 2007)
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Catechol-O-methyltransferase
Val158Met polymorphism
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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
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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)
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Provides insight into COMT mechanisms
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As before with α7 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
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Assessment of PPI, 5-CSR , and odor span task
Sensitivity to environmental insults
Dissecting the watershed model
Two steps forward
DRUG
Met
Behaviors
PFC
dopamine
clearance
Val
Environment
Impact
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One gene at a time
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Conclusion for
Genetic Models
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Positives:
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↑ in number & sophistication for the human allele
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Are developmental in nature
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Allow for:
 Genetic
 Drug
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+ environmental models
X gene interaction studies
Negatives:
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Cognitive tasks not as well developed
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Lesion and pharmacological validation required
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Thanks for listening
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Thanks
Mark A Geyer
Vickie Risbrough
Susan Powell
Jessica Meves
Richard ‘Pete’ Sharp
Mahalah Buell
Tammy Zhou
Christine Scott
Sorana Caldwell
NARSAD Young
Investigator Award
2008-2010
Pala Grant Awards
Dilip V. Jeste
David Braff
Lisa Eyler
Greg Asgaard
Greg Light
Anthony Rissling
R21 funding to
validate the 5C-CPT
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