ANIMAL MODELS OF NEUROPSYCHIATRIC DISORDERS

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Quantitative trait loci analysis for genes linked to deficits in prepulse inhibition is ongoing. Prepulse inhibiton is a measure of sensorimotor gating which is abnormal in several neuropsychiatric disorders, including schizophrenia. Normal prepulse inhibition in AKR mice and impaired prepulse inhibition in C57BL/6J mice provides a basis for discovering genes linked to this trait in mice, that may indicate candidate genes to investigate in schizophrenia. AKR x C57BL/6J F2 mice were behaviorally characterized by Richard Paylor and genotyped by collaborators Alan Sanders and Pablo Gejman. Several suggestive chromosomal loci were identified in the 10% extremes of the behavioral distribution. The entire test population of 500 mice was then genotyped with a denser set of microsatellite markers around the suggestive loci. Suggestive loci are now being further explored in the F5 generation bred from individual mice at the extremes of the prepulse phenotyping distribution. Our Section collaborates with several molecular geneticists laboratories on behavioral phenotyping of transgenic and knockout mice with mutations in genes expressed in the brain, relevant to our research interests. Over the past year, we have developed rigorous methods for quantitating preliminary observations of general health, home cage behaviors, sensory abilities, and motor functions, to ensure that the mutant line has no gross physical defects that would produce false positives. Further, we have developed new behavioral tasks for mice, and adapted rat behavioral tasks for mice, which reduce false negatives in the first characterization of a new mutation, through analysis of a constellation of ccomplementary tests for each behavioral domain, e.g. memory, feeding, anxiety, social behaviors, motor coordination. These methods are currently being applied to the characterization of a) a dopamine D5 receptor knockout mouse generated by Dave Sibley, NINDS, being tested for behavioral phenotype by our postdoctoral fellow Andrew Holmes;b) a knockout mouse deficient in a hippocampal development gene, Lhx5, generated by Heiner Westphal, NICHD, tested last year for behavioral phenotype by Richard Paylor;c) a knockout mouse model of Tay-Sachs disease generated by Rick Proia, NIDDK, tested last year by Michael McDonald, tested this year by postdoctoral fellow Tsuyoshi Miyakawa. This Tay-Sachs mouse model is proving amenable to testing of potential therapeutics for this lethal human genetic disease. Bone marrow transplants into the null mutants produced a dramatic delay in onset of the behavioral syndrome and of lethality. PUBLICATION: Norflus, Tifft, McDonald, Goldstein, Crawley, Hoffmann, Sandhoff, Suzuki, Proia: Bone marrow transplantation prolongs life span and ameliorates neurologic manifestations in Sandhoff disease mice. Journal of Clinical Investigation 101: 1881-1888, 1998.d) a knockout mouse deficient in neurogranin, a substrate of calmodulin which regulates neuronal calcium flux, generated by Dr. Huang, NICHD, behavioral testing being conducted by Tsuyoshi Miyakawae) M3 and M5 muscarinic receptor knockout mice, generated by Jurgen Wess, NIDDK, behavioral testing being conducted by Tsuyoshi Miyakawa. - Behavioral genetics Quantitative trait loci Prepulse inhibition Schizophrenia Transgenic and knockout mice