Animal Models of Schizophrenia: NRG-erbB Function

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种基于gila功能障碍的精神分裂症的良好模型，该模型可以用作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有待深入研究，因为神经胶质细胞的功能失调可能对突触传递，特别是海马和新皮层的谷氨酸传递有显著影响。这一研究领域在精神分裂症中很少受到关注，因为精神分裂症的主要神经病理学尚未确定。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，我们建议研究两种转基因小鼠，其中

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.