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: 7720351
• 负责人: PASQUALE MANZERRA
• 金额: $ 16.46万
• 依托单位: UNIVERSITY OF SOUTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720351
• 关键词: Animals; Antipsychotic Agents; Behavioral; Characteristics; Cognitive; Computer Retrieval of Information on Scientific Projects Database; Digit structure; Disinhibition; Functional disorder; Funding; Glutamate Receptor; Grant; Head; Human; Individual; Institution; Modeling; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 NMDA receptor; Nerve Degeneration; Phencyclidine; Physiological; Proteins; Psychotic Disorders; Rattus; Research; Research Personnel; Resources; Rodent; Role; Schizophrenia; Site; Source; Stereotyped Behavior; Symptoms; Synapses; United States National Institutes of Health; Withdrawal; density; frontal lobe; postsynaptic; receptor; receptor function; social

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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 苯环利定(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一过性精神病，并会加剧精神分裂症患者的精神病。当给啮齿动物注射五氯苯酚时，会引起刻板印象的行为，包括无情的摇头、咬手指和社交退缩，这些都是人类精神分裂症的负面迹象。最近的发现表明谷氨酸受体在精神分裂症中发挥了作用。本项目中的研究将检验这样一种假设，即NMDA受体功能降低会导致不受调节的兴奋、去抑制，并最终导致神经元退化，从而导致精神分裂症的异常认知和行为表现。精神分裂症期间NMDA受体功能的降低指导了本研究提出的两个主要假说：(1)精神分裂症的谷氨酸受体功能障碍依赖于额叶皮质NMDA受体亚单位组成的变化；(2)非典型抗精神病药物通过恢复NMDA受体功能或绕过NMDA功能障碍的细胞机制来减轻精神分裂症的症状。具体地说，我们将检查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受体的NR1亚单位是否减少。我们还将测定PCP治疗的大鼠与对照组和抗精神病药物治疗的动物相比，额叶皮质突触部位NMDA受体的亚单位组成，以及检测突触后密度(PSD)内其他蛋白质的变化。我们研究的主要目的是为了从根本上了解精神分裂症及其背后的生理机制？S。