P5-Mouse Phenotyping

该项目致力于小鼠模型系统的开发和表征， 精神分裂症患者髓鞘和少突胶质细胞相关（OMR）基因表达缺陷。 将评估几种不同的遗传修饰小鼠模型系统（例如，震颤，MAG， PTPRZ1和Olig2。将筛选这些小鼠模型系统中的每一个的以下表达缺陷： OMR基因使用一组我们已经证明在精神分裂症中受到差异影响的OMR基因。 那些在至少3个已知受影响的OMR基因上证明基因表达缺陷的人， 精神分裂症将被评估为行为缺陷。行为表型测试组合将 包括简单（例如，反射，运动，平衡，感觉）以及复杂的 （学习、记忆、惊吓、惊吓前脉冲抑制、社会交往、焦虑）行为。加上 这些纯粹的行为测试将是药理学探针，以确定药理学特征是否 通常被视为精神分裂症啮齿动物模型的原型，也由OMR基因证明 缺陷小鼠一旦确定了“最适合”的模式系统，将对其进行纵向研究， 确定从3个月大到18岁的基因表达和行为缺陷的演变 月龄。此外，激光捕获显微切割技术将用于研究基因 在鉴定的细胞群中表达。在与项目1的合作中，“最适合”的鼠标模型系统将是 在对应于行为测试的年龄，通过DTI在体内系统地成像。合作 在项目3中，将研究来自其他小鼠的脑组织标本中少突胶质细胞的变化， 增殖、分化和存活。在这方面已经取得了重大进展。所有 在我们的研究中，已经对行为测试范例进行了试验，并对用于小鼠的参数进行了优化。 表型分析设施（随附结果和描述）。提出的4种动物模型系统中有3种 使用（Quaking，Olig2和MAG）。一些研究已经完成， 已经建立了小鼠和群体以进行更大规模的研究。

This project is dedicated to the development and characterization of mouse model systems that best reflect the myelin and oligodendrocyte related (OMR) gene expression deficits in persons with schizophrenia. Several different genetically modified mouse model systems will be evaluated (e.g., Quaking, MAG, PTPRZ1, and Olig2. Each of these mouse model systems will be screened for deficits in the expression of OMR genes using a panel of OMR genes that we have shown to be differentially affected in schizophrenia. Those that evidence gene expression deficits on at least 3 OMR genes known to be affected in schizophrenia will then be assessed for behavioral deficits. The behavioral phenotyping test battery will include screening tests of simple (e.g., reflexes, locomotion, balance, sensation) as well as complex (learning, memory, startle, prepulse inhibition of startle, social interaction, anxiety) behaviors. Coupled with these purely behavioral tests will be pharmacological probes to ascertain whether pharmacological profiles commonly viewed as prototypical for rodent models of schizophrenia are also evidenced by the OMR gene deficient mice. Once "best-fit" model systems have been identified, they will be studied longitudinally to ascertain the evolution of gene expression and behavioral deficits from 3 months of age through to 18 months of age. In addition, laser capture microdissection techniques will be employed to investigate gene expression in identified cell groups. In collaboration with Project 1, the "best-fit" mouse model system will be systematically imaged by DTI in vivo at ages corresponding to those for behavioral testing. In collaboration with Project 3, brain tissue specimens from additional mice will be studied for changes in oligodendroglial proliferation, differentiation and survival. Significant progress has already been made in this regard. All of the behavioral test paradigms have been piloted and parameters have been optimized for use in mice in our phenotyping facility (results and descriptions appended). Three of the 4 animal model systems proposed for use (Quaking, Olig2, and MAG) have been obtained. Some studies have already been completed in these mice and colonies have been established to enable more large scale studies.