SYNAPTIC LOCALIZATION OF NMDA RECEPTOR PCP MODEL OF SCHIZOPHRENIA

NMDA受体突触定位精神分裂症PCP模型

• 批准号: 7381104
• 负责人: Josette Lindahl
• 金额: $ 11.6万
• 依托单位: UNIVERSITY OF SOUTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381104
• 关键词: SYNAPTIC; LOCALIZATION; NMDA; RECEPTOR; PCP

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.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。 Phencyclidine (PCP) 是 NMDA 谷氨酸受体的非竞争性拮抗剂。它会在正常人中产生短暂的精神病，并加剧精神分裂症患者的精神病。当啮齿动物服用五氯苯酚时，五氯苯酚会引发刻板行为，包括不断摇头、啃手指和社交退缩，这些都是人类精神分裂症的负面症状。最近的研究结果表明谷氨酸受体在精神分裂症中发挥作用。该项目的研究将检验这样的假设：NMDA 受体功能降低会导致不受调节的兴奋、去抑制，并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。精神分裂症期间 NMDA 受体功能的降低引导了本研究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取决于额叶皮质中 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来减轻精神分裂症的症状。具体来说，我们将检查与对照和非典型抗精神病药治疗的动物相比，PCP 治疗的大鼠额叶皮层突触位点的 NMDA 受体 NR1 亚基是否减少。我们还将确定经 PCP 治疗的大鼠与对照组和精神安定药治疗的动物相比，额叶皮层突触部位 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。我们研究的主要目标是促进对精神分裂症及其潜在生理机制的基本了解。