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. The full data set is now being analyzed statistially for significant linkages. Suggestive loci are being further explored in the F5 generation, selectively bred from individual mice at the extremes of the distribution for the prepulse inhibition behavioral phenotype. 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 in animal models of neuropsychiatric diseases. Over the past years, we have developed and refined a multitiered strategy for behavioral phenotyping. Rigorous methods for quantitate observations of general health, home cage behaviors, tests for sensory abilities, and motor functions, to ensure that the mutant line has no gross physical defects that would produce false positives on more complex behavioral tasks. Further, we have developed new behavioral tasks for mice, and adapted rat behavioral tasks for mice. The strategy for hypothesis testing reduces false negatives in the first characterization of a new mutant line. A constellation of ccomplementary tests is conducted for each behavioral domain, e.g. memory, feeding, anxiety, social behaviors, motor coordination. PUBLICATION: Crawley JN (1999) Behavioral phenotyping of transgenic and knockout mice. Brain Research Special Issue on Knockouts and Mutants 835:18-26.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; (PUBLICATION submitted)b) 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 Miyakawac) M3 and M5 muscarinic receptor knockout mice, generated by Jurgen Wess, NIDDK, behavioral testing being conducted by Tsuyoshi Miyakawa. (PUBLICATION submitted)d) Serotonin transporter knockout mouse, generated by Dennis Murphy, NIMH, behavioral testing being conducted by Andrew Holmes.
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