SYNAPTIC LOCALIZATION OF NMDA RECEPTOR PCP MODEL OF SCHIZOPHRENIA

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 苯环己哌啶（PCP）是一种非竞争性NMDA谷氨酸受体拮抗剂。 它在正常人中产生短暂的精神病，并加重精神分裂症患者的精神病。当给啮齿动物服用五氯苯酚时，五氯苯酚会消除刻板行为，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阴性症状。最近的发现暗示谷氨酸受体在精神分裂症中的作用。本项目中的研究将检验这一假设，即NMDA受体功能降低会导致兴奋失控、抑制解除，最终导致神经元变性，从而导致精神分裂症特征性的异常认知和行为表现。精神分裂症时NMDA受体功能的降低引导了本研究中提出的两个主要假设：（1）精神分裂症中谷氨酸受体功能障碍依赖于额叶皮层中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的症状。具体来说，我们将研究是否NR 1亚单位的NMDA受体减少在突触部位PCP治疗大鼠额叶皮层相比，控制和非典型的神经阻滞剂治疗的动物。我们还将确定亚基组成的NMDA受体在突触部位在PCP治疗的大鼠额叶皮层相比，对照组和神经阻滞剂治疗的动物，以及检查其他蛋白质内的突触后密度（PSD）的变化。我们研究的主要目的是有助于对精神分裂症的基本了解，它？的潜在生理机制。

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.