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）：此申请是针对NIMH PA-02-027提交的。这笔赠款的目的是基于吉拉功能障碍找到一个精神分裂症的良好模型，该模型可以用作抗精神病药的筛查工具。对神经胶质在精神分裂症遗传模型中的作用的强烈研究过于逾期，因为预计吉拉的功能故障对突触传播有明显影响，尤其是海马和新肌肉中的谷氨酸传播。该研究领域在精神分裂症中很少关注，这是一种尚未确定的主要神经病理学的疾病。鉴于最近发现的神经蛋白1（NRG1）基因和该疾病的关联，我们建议研究两条转基因小鼠，其中 NRG受体ERBB2、3和4的功能已通过插入少突胶质细胞或星形胶质细胞中的显性负ERBB突变而被禁用。该赠款的第一阶段将集中于对这些转基因功能障碍的这些转基因线的验证，作为精神分裂症或精神分裂症症状的模型。第一阶段的终点度量基于精神分裂症的假定动物模型的已知表型（行为多动症和对惊吓的抑制作用受损）和其他涵盖精神分裂症的负，正和认知症状的行为措施。我们将使用药理学来加剧或挽救可能的行为差异，并表征神经解剖学和神经递质功能的基本方面，该功能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是，它们在神经肌肉连接处避免了NRG1-ERBB信号传导，这可能会混淆行为分析。如果成功，第二阶段将跟进模型对典型和非典型抗精神病药的药理敏感性的全面表征，以及这些行为，神经递质和神经植物学特征的恢复时间过程，这些特征将模型与野生类型（WT）控制（在IS IS IS INS SCH上都具有较高的范围相同，则与该模型相同。这样的模型将允许基于新颖和标准化学的抗精神病药治疗测试，并将定义最佳治疗治疗的首选发育时间和药物状态。