Animal Models of Schizophrenia: NRG-erbB Function

精神分裂症动物模型：NRG-erbB 功能

• 批准号: 6737260
• 负责人: Daniela Brunner
• 金额: $ 25万
• 依托单位: PSYCHOGENICS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-13 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6737260
• 关键词: SDS polyacrylamide gel electrophoresis; autoradiography; cognition; disease /disorder model; gene targeting; genetically modified animals; glia; immunocytochemistry; laboratory mouse; model design /development; neuregulins; neuropathology; neuropsychological tests; neurotransmitters; polymerase chain reaction; receptor expression; schizophrenia; short term memory

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.

描述（由申请人提供）：本申请是根据NIMH PA-02-027提交的。这项资助的目标是找到一个基于神经胶质细胞功能障碍的精神分裂症的良好模型，可以作为抗精神病药物的筛选工具。神经胶质细胞在精神分裂症遗传模型中的作用的深入研究早该进行了，因为神经胶质细胞的功能失常预计会对突触传递，特别是海马体和新皮层中谷氨酸的传递产生显著影响。这一领域的研究在精神分裂症中很少受到关注，精神分裂症是一种主要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（NRG 1）基因和这种疾病的关联，我们建议研究两种转基因小鼠，其中 通过在少突胶质细胞或星形胶质细胞中插入显性负性erbB突变，NRG受体erbB 2、3和4的功能已经丧失。第一阶段的拨款将集中在验证这些转基因系的吉拉功能障碍作为一个模型的精神分裂症或精神分裂症的症状。I期的终点指标基于精神分裂症推定动物模型的已知表型（行为多动和惊吓前脉冲抑制受损）和涵盖精神分裂症阴性、阳性和认知症状的其他行为指标。我们将使用药理学来加剧或挽救可能的行为差异，并将表征神经解剖学和神经递质功能的基本方面，对应于精神分裂症患者的功能障碍。我们选择追求的细胞特异性模型的主要优点在于它们避免了神经肌肉接头处的NRG 1-erbB信号传导，这可能会混淆行为分析。如果成功，II期将随访模型对典型和非典型抗精神病药物的药理学敏感性的完整表征，以及将模型与其野生型（WT）对照区分开的那些行为、神经递质和神经解剖学特征的恢复时间过程，如I期所示。商业价值：开发改良的精神分裂症动物模型是该领域的一个极高优先级。这些模型将允许基于新的和标准的化学物质测试抗精神病药物治疗，并将定义最佳治疗性治疗的优选开发时间和药物方案。