GLUTAMATE RECEPTOR SUBUNIT FUNCTION AND SCHIZOPHRENIA

描述(申请人提供)：精神分裂症是一种衰弱的神经发育疾病，不分种族或民族界限。对其病因学的初步研究集中在高多巴胺能活性上，这是基于临床观察，即多巴胺阻断药物可以减轻阳性精神病症状。最近的发现表明谷氨酸受体在精神分裂症中的作用。这些研究表明，NMDA受体功能降低刺激突触内异常高的谷氨酸释放，从而导致不受调节的兴奋、抑制通路的去抑制和神经元的退化。这种谷氨酸能神经传递受损可能与精神分裂症特有的认知、行为和记忆功能异常有关。精神分裂症的NMDA受体功能低下理论指导了本研究提出的两个假说：(1)精神分裂症的谷氨酸受体功能障碍依赖于特定脑区NMDA和AMPA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功能或绕过NMDA功能障碍的细胞机制来减轻精神分裂症症状。我们研究的主要目标是对精神分裂症及其潜在的生理机制有一个基本的了解。我们将通过检查检验这些假设的三个目标来为这个知识库做出贡献。目的：应用免疫细胞化学和光镜技术对正常大鼠脑和精神分裂症大鼠脑内NMDA和AMPA谷氨酸受体亚基进行定位。目的：探讨非典型抗精神病药物对正常大鼠、精神分裂症大鼠、正常抗精神病药物治疗大鼠及精神分裂症大鼠脑内N-甲基-D-天冬氨酸和AMPA受体亚基组成的影响。目的：研究非典型抗精神病药物对正常大鼠、正常抗精神病大鼠、PCP精神病大鼠和PCP精神病大鼠脑内NMDA和AMPA介导的谷氨酸能神经递质的影响及其可能的生理机制。虽然这项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，但这项提议的长期意图是建立我作为一名临床科学家的职业生涯，并有可能发展为一名独立研究人员。

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.