GLUTAMATE RECEPTOR SUBUNIT FUNCTION AND SCHIZOPHRENIA

描述（由申请人提供）：精神分裂症是一种使人衰弱的神经发育疾病，不尊重种族或民族界限。其病因学的初步研究集中在基于多巴胺阻断药物减少阳性精神病症状的临床观察的高多巴胺能活性。最近的发现暗示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，随后导致不受调节的兴奋，抑制途径的去抑制和神经元变性。这种受损的多巴胺能神经传递可能与精神分裂症特有的异常认知、行为和记忆功能有关。精神分裂症的NMDA受体功能减退理论指导了本研究中提出的两个假设：（1）精神分裂症中谷氨酸受体功能障碍依赖于特定脑区NMDA和AMPA受体亚基组成的改变;（2）非典型精神抑制剂通过恢复NMDA功能或规避NMDA功能障碍的细胞机制减轻精神分裂症症状。我们研究的主要目标是有助于对精神分裂症及其潜在生理机制的基本理解。我们将通过检验检验这些假设的三个目标来为这一知识基础做出贡献。目标1：应用免疫细胞化学和光镜技术对正常大鼠和PCP致精神病大鼠脑内NMDA和AMPA谷氨酸受体亚单位进行定位。目标2：探讨非典型抗精神病药对正常大鼠、PCP致精神病大鼠、正常抗精神病药治疗大鼠和PCP致精神病药治疗大鼠脑内NMDA和AMPA受体亚单位相对组成的影响。目标3：在正常、正常抗精神病药治疗、PCP-精神病诱导和PCP-精神病诱导的抗精神病药治疗大鼠脑中，研究可能是非典型抗精神病药对NMDA和AMPA介导的多巴胺能神经传递影响的潜在生理作用机制。虽然K 08申请的总体科学目标是阐明谷氨酸受体在精神分裂症病理生理学中的作用，但该提案的长期目的是建立我作为临床科学家的职业生涯，并有可能发展为独立研究人员。

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.