Animal Models of Schizophrenia: NRG-erbB Function

描述(申请人提供)：本申请是根据NIMH PA-02-027的要求提交的。这笔赠款的目标是找到一种基于Gila功能障碍的精神分裂症的良好模型，可以用作抗精神病药物的筛查工具。早该对神经胶质细胞在精神分裂症遗传模型中的作用进行深入研究，因为功能失常的Gila预计会对突触传递，特别是海马体和新皮质中的谷氨酸传递产生显著影响。这一领域的研究在精神分裂症方面几乎没有受到关注，精神分裂症是一种主要的神经病理学尚未确定的疾病。鉴于最近发现的神经调节蛋白1(NRG1)基因与这种疾病的关联，我们建议研究两个转基因小鼠系，其中 通过在少突胶质细胞或星形胶质细胞中插入显性的负erb B突变，NRG受体erbB2、3和4的功能已被禁用。这笔赠款的第一阶段将集中于验证这些GILA功能障碍转基因品系是否为精神分裂症或精神分裂症症状的模型。第一阶段的终点测量是基于假定的精神分裂症动物模型的已知表型(行为多动和惊吓的脉搏前抑制受损)以及涵盖精神分裂症的阴性、阳性和认知症状的其他行为测量。我们将使用药理学来加剧或挽救可能的行为差异，并将表征与报告的精神分裂症患者功能障碍相对应的神经解剖学和神经递质功能的基本方面。我们选择追求的细胞特异性模型的主要优势在于，它们避免了神经肌肉连接处的NRG1-erbB信号，这可能会扰乱行为分析。如果成功，第二阶段将进一步全面描述模型(S)对典型和非典型抗精神病药物的药理敏感性，以及在第一阶段中发现的将该模型与其野生型(WT)对照区分开来的那些行为、神经递质和神经解剖学特征的恢复时间过程。商业价值：该领域开发改进的精神分裂症动物模型是极其优先的。这些模型将允许基于新的和标准的化学物质来测试抗精神病药物治疗，并将确定最佳治疗方法的首选开发时间和药物制度。

DESCRIPTION (provided by applicant): This application is submitted in response to NIMH PA-02-027. The goal of this grant is to find a good model for schizophrenia based on gila dysfunction that can be used as a screening tool for antipsychotic drugs. An intense investigation of the role of glia in a genetic model of schizophrenia is overdue, since malfunctioning gila is expected to have a marked effect on synaptic transmission, especially glutamate transmission in the hippocampus and neorcortex. This area of study has received little attention in schizophrenia, a disease in which the primary neuropathology has yet to be identified. In light of the recently found association of the neuregulin 1 (NRG1) gene and this disorder, we propose to investigate two lines of transgenic mice in which the function of the NRG receptors erbB2, 3 and 4 has been disabled through insertion of a dominant negative erbB mutation in either oligodendrocytes or astrocytes. Phase I of this grant will concentrate on the validation of these transgenic lines of gila dysfunction as a model of schizophrenia or of schizophrenic symptoms. The endpoint measures for Phase I are based on the known phenotypes of putative animal models of schizophrenia (behavioral hyperactivity and impaired prepulse inhibition of startle) and other behavioral measures covering negative, positive and cognitive symptoms of schizophrenia. We will use pharmacology to exacerbate or rescue possible behavioral differences and will characterize basic aspects of neuroanatomy and neurotransmitter function corresponding to reported dysfunctions in schizophrenic patients. The main advantage of the cell-specific models we chose to pursue resides in that they spare NRG1-erbB signaling at neuromuscular junctions, which could confound the behavioral analysis. If successful, Phase II will follow up with a full characterization of the pharmacological sensitivity of the model(s) to typical and atypical antipsychotic drugs, and the time course of recovery of those behavioral, neurotransmitter and neuroanatomical characteristics that distinguish the model from its wild type (WT) control, as found in Phase I. Commercial Value: It is an extremely high priority for the field to develop improved animal models of schizophrenia. Such models will allow testing of antipsychotic treatments based on novel and standard chemistries, and will define the preferred developmental time and drug regime for an optimal therapeutic treatment.