SYNAPTIC LOCALIZATION OF NMDA RECEPTOR PCP MODEL OF SCHIZOPHRENIA

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。苯环利定（PCP）是NMDA谷氨酸受体的非竞争性拮抗剂。它使正常人产生短暂性精神病，使精神分裂症患者的精神病加重。当给啮齿动物服用PCP时，会引起刻板的行为，包括不停地摇头、啃手指和社交退缩，这些都是人类精神分裂症的负面迹象。最近的发现暗示了谷氨酸受体在精神分裂症中的作用。本项目的研究将检验NMDA受体功能降低导致不受调节的兴奋、去抑制，并最终导致神经变性，从而导致精神分裂症特征的异常认知和行为表现的假设。精神分裂症患者NMDA受体功能的降低指导了本研究提出的两个主要假设：(1)精神分裂症患者谷氨酸受体功能障碍依赖于额叶皮层NMDA受体亚基组成的改变；(2)非典型抗精神病药通过恢复NMDA受体功能或规避NMDA功能障碍的细胞机制减轻精神分裂症症状。具体来说，我们将研究与对照组和非典型抗精神病药物治疗的动物相比，pcp治疗的大鼠额叶皮质突触部位的NMDA受体NR1亚基是否减少。我们还将确定与对照组和抗精神病药治疗的动物相比，pcp治疗的大鼠额叶皮质突触部位NMDA受体的亚基组成，并检查突触后密度（PSD）内其他蛋白质的变化。我们研究的主要目的是促进对精神分裂症及其疾病的基本理解。S潜在的生理机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Phencyclidine (PCP) is a non-competitive antagonist of the NMDA glutamate receptor. It produces transient psychosis in normal individuals and exacerbates psychosis in schizophrenics. When administered to rodents, PCP elicits stereotyped behaviors including unrelenting head swaying, digit gnawing and social withdrawal, that are representative of negative signs of schizophrenia in humans. Recent findings have implicated a role for glutamate receptors in schizophrenia. The studies in this project will examine the hypothesis that reduced NMDA receptor function leads to unregulated excitation, disinhibition, and ultimately to neuronal degeneration that contribute to the abnormal cognitive and behavioral manifestations characteristic of schizophrenia. Reduced NMDA receptor function during schizophrenia guides two main hypotheses proposed in this research: (1) that glutamate receptor dysfunction in schizophrenia is dependent on alterations in NMDA receptor subunit composition in the frontal cortex; and (2) that atypical neuroleptics reduce symptoms of schizophrenia through cellular mechanisms that either restore NMDA receptor function or circumvent NMDA dysfunction. Specifically, we will examine whether NR1 subunits of the NMDA receptor are reduced at synaptic sites in frontal cortex of PCP-treated rats compared to control and atypical neuroleptic-treated animals. We will also determine the subunit composition of NMDA receptors at synaptic sites in frontal cortex of PCP-treated rats compared to controls and neuroleptic-treated animals, as well as examine alterations in other proteins within the postsynaptic density (PSD). The primary objective of our research is to contribute to a fundamental understanding of schizophrenia and it?s underlying physiological mechanisms.