ANIMAL MODELS OF NEUROPSYCHIATRIC DISORDERS

与脉冲前抑制缺陷相关的基因的数量性状位点分析正在进行中。脉冲前抑制是一种感觉运动门控的测量方法，在包括精神分裂症在内的一些神经精神疾病中是异常的。AKR小鼠的正常预脉冲抑制和C57BL/6J小鼠的预脉冲抑制受损，为发现与小鼠这一特性相关的基因提供了基础，这些基因可能为研究精神分裂症提供候选基因。Richard Paylor对AKR x C57BL/6J F2小鼠进行了行为表征，Alan Sanders和Pablo Gejman对其进行了基因分型。在10%的极端行为分布中发现了几个暗示性的染色体位点。然后用一组更密集的微卫星标记围绕提示位点对整个500只小鼠进行基因分型。目前正在对全部数据集进行统计分析，以寻找重要的联系。在F5代中，在脉冲前抑制行为表型分布的极端情况下，选择性地从个体小鼠中培育出具有暗示意义的基因座。我们科与几个分子遗传学家实验室合作，研究大脑中表达基因突变的转基因和敲除小鼠的行为表型，这与我们在神经精神疾病动物模型方面的研究兴趣相关。在过去的几年中，我们已经开发并完善了行为表型的多层策略。采用严格的方法对一般健康状况、家庭笼内行为、感觉能力和运动功能进行定量观察，以确保突变品系没有严重的身体缺陷，不会在更复杂的行为任务中产生假阳性。此外，我们还开发了新的小鼠行为任务，并为小鼠调整了大鼠行为任务。假设检验的策略减少了在新突变系的第一次表征中的假阴性。对每个行为领域进行一系列补充测试，例如记忆、进食、焦虑、社会行为、运动协调。出版物：Crawley JN（1999）转基因和基因敲除小鼠的行为表型。脑研究特刊：敲除和突变835:18-26。这些方法目前正被应用于：a)由Dave Sibley， NINDS产生的多巴胺D5受体敲除小鼠，由我们的博士后研究员Andrew Holmes进行行为表型测试；b)基因敲除小鼠缺乏神经颗粒蛋白（一种调节神经元钙通量的钙调素底物，由Dr. Huang， NICHD产生，行为测试由Tsuyoshi miyakawc进行）M3和M5毒碱受体基因敲除小鼠，由Jurgen Wess， NIDDK产生，行为测试由Tsuyoshi Miyakawa进行。d)血清素转运蛋白敲除小鼠，由NIMH的Dennis Murphy制造，行为测试由Andrew Holmes进行。

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.