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。在脉冲前表型分布极端的个体小鼠培育的F5代中，目前正在进一步探索暗示性位点。我们部门与几个分子遗传学家实验室合作，研究与我们的研究兴趣相关的大脑中表达基因突变的转基因和敲除小鼠的行为表型。在过去的一年里，我们开发了严格的方法来量化一般健康，家庭笼行为，感觉能力和运动功能的初步观察，以确保突变系没有可能产生假阳性的严重生理缺陷。此外，我们为小鼠开发了新的行为任务，并为小鼠调整了大鼠行为任务，通过对每个行为领域（如记忆、喂养、焦虑、社交行为、运动协调）的互补测试进行分析，减少了新突变首次表征的假阴性。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)由NICHD的Heiner Westphal产生的海马发育基因Lhx5缺失的敲除小鼠，Richard Paylor去年对其进行了行为表型测试；c)由NIDDK的Rick Proia制造的一种Tay-Sachs病基因敲除小鼠模型，去年由Michael McDonald测试，今年由博士后Tsuyoshi Miyakawa测试。这种泰-萨克斯小鼠模型被证明适合于测试这种致命的人类遗传疾病的潜在治疗方法。将骨髓移植到零突变体中，显著延缓了行为综合症的发作和致死率。发表：Norflus， Tifft, McDonald, Goldstein, Crawley, Hoffmann, Sandhoff, Suzuki， Proia：骨髓移植延长了Sandhoff病小鼠的寿命并改善了神经系统表现。中国临床医学杂志（英文版），1998。d)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制造，行为测试由Tsuyoshi miyakawe进行）M3和M5毒碱受体基因敲除小鼠，由Jurgen Wess， NIDDK制造，行为测试由Tsuyoshi Miyakawa进行。-行为遗传学数量性状基因座脉冲前抑制精神分裂症转基因和基因敲除小鼠

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