GLUTAMATE RECEPTOR SUBUNIT FUNCTION AND SCHIZOPHRENIA

谷氨酸受体亚基功能与精神分裂症

• 批准号: 6547751
• 负责人: Josette Lindahl
• 金额: $ 9.19万
• 依托单位: UNIVERSITY OF SOUTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-21 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6547751
• 关键词: AMPA receptors; NMDA receptors; antipsychotic agents; brain electrical activity; cerebellum; disease /disorder etiology; disease /disorder model; frontal lobe /cortex; glutamates; immunocytochemistry; inhibitor /antagonist; laboratory rat; light microscopy; neural transmission; neuropharmacology; neurophysiology; pharmacokinetics; phencyclidine; protein localization; protein structure function; psychopharmacology; receptor binding; receptor expression; schizophrenia; single cell analysis; western blottings

DESCRIPTION (provided by applicant): Schizophrenia is a debilitating neurodevelopmental illness that honors no racial or ethnic boundaries. Initial research into its etiology has focused on hyperdopaminergic activity based on clinical observations that dopamine blocking drugs diminish positive psychotic symptoms. Recent findings have implicated the role of glutamate receptors in schizophrenia. These studies propose that reduced NMDA receptor function stimulates abnormally high glutamate release within the synapse, which subsequently leads to unregulated excitation, disinhibition of inhibitory pathways, and neuronal degeneration. Such impaired glutamatergic neurotransmission is potentially associated with the abnormal cognitive, behavioral and memory functions characteristic of schizophrenia. The NMDA receptor hypofunction theory of schizophrenia guides two hypotheses proposed in this research: (1) Glutamate receptor dysfunction in schizophrenia is dependent on alterations in NMDA and AMPA receptor subunit composition in specific brain regions; and (2) Atypical neuroleptics reduce schizophrenic symptoms through cellular mechanisms that either restore NMDA function or circumvent NMDA dysfunction. The primary objective of our research is to contribute to a fundamental understanding of schizophrenia and it's underlying physiological mechanisms. We will contribute to this knowledge base by examining three aims that test these hypotheses. AIM 1: To localize NMDA and AMPA glutamate receptor subunits by immunocytochemistry and light microscopy in normal rat brains and PCP-psychosis induced rat brains. AIM 2: To elucidate the effects of atypical neuroleptics on relative NMDA and AMPA receptor subunit composition in normal rat, PCP-psychosis induced rat, normal neuroleptic treated rat and neuroleptic treated, PCP-psychosis induced rat brains. AIM 3: To examine potential physiological mechanisms of action that may underlie the effects of atypical neuroleptics on NMDA and AMPA-mediated glutamatergic neurotransmission in normal, normal neuroleptic treated, PCP-psychosis induced and PCP-psychosis induced neuroleptic treated rat brains. While the overall scientific goal of this K08 application is to elucidate the role of glutamate receptors in schizophrenia's pathophysiology, the long-term intent of this proposal is to establish my career as a clinical scientist with the potential to develop as an independent researcher.

描述（由申请人提供）：精神分裂症是一种令人衰弱的神经发育疾病，没有尊重种族或种族界限。基于多巴胺阻止药物减少阳性精神病症状的临床观察结果，对其病因的初步研究集中在高巴博宁活性上。最近的发现暗示了谷氨酸受体在精神分裂症中的作用。这些研究表明，降低NMDA受体功能会刺激突触中异常高的谷氨酸释放，这随后导致不受管制的激发，抑制途径的抑制作用和神经元变性。这种受损的谷氨酸能神经传递可能与精神分裂症的异常认知，行为和记忆功能有关。精神分裂症的NMDA受体功能障碍理论指导了这项研究中提出的两个假设：（1）精神分裂症中的谷氨酸受体功能障碍取决于特定特定脑区域中NMDA和AMPA受体亚基组成的改变； （2）非典型神经疗法通过恢复NMDA功能或避免NMDA功能障碍的细胞机制来减少精神分裂症。我们研究的主要目的是为精神分裂症及其基本的生理机制做出基本理解。我们将通过研究测试这些假设的三个目标来为这一知识库做出贡献。目标1：通过免疫细胞化学和光学显微镜在正常大鼠大脑和PCP心理诱导的大鼠大脑中定位NMDA和AMPA谷氨酸受体亚基。目的2：为了阐明非典型神经摄影对正常大鼠的相对NMDA和AMPA受体亚基组成的影响，PCP心理诱导的大鼠，正常的神经摄影治疗的大鼠和受PCP心理治疗，PCP心理治疗，PCP心理学，PCP心理学，诱导的大鼠脑。目的3：检查可能在正常的，正常的神经摄影治疗，PCP精神病诱导的和PCP-精神病诱导的神经肽治疗诱导的神经肽治疗诱导的神经疗法治疗中，非典型神经肽对NMDA和AMPA介导的谷氨酸神经传递的影响的潜在生理机制。尽管该K08应用的总体科学目标是阐明谷氨酸受体在精神分裂症的病理生理学中的作用，但该提案的长期意图是确定我作为临床科学家的职业，有可能发展为独立研究者。