Roles of NMDA receptors in schizophrenia pathological process

描述（由申请人提供）：精神分裂症可能是最令人痛苦和致残的精神障碍。它影响了近1%的人口。虽然这种疾病的病理过程尚不清楚，但在过去的几十年里，人们在解开这个谜团方面取得了显著的进展。根据对精神分裂症患者大脑的死后研究，现在很清楚，前脑中的某些抑制性神经元被选择性地破坏了。此外，一组解离性麻醉剂，如苯环利定（PCP，雪尼，也称为“天使之尘”）及其相关化合物MK-801和氯胺酮，可在手术患者和健康志愿者中产生广泛的精神分裂症样症状，如疏远、思维障碍、幻觉和精神病。这些药物也可引起动物模型前脑抑制性中间神经元的类似损伤。由于这些药物也是NMDA受体拮抗剂，因此提出了NMDA受体和抑制性中间神经元功能减退假说，以解释精神分裂症的病理过程。这一有趣的假设引起了广泛的关注，但支持这一假设的直接证据仍然缺乏。在这个提议中，我们假设前额皮质中间神经元亚群的受体特性是独特的组织，这些特性使它们极易受到导致精神分裂症的环境因素的影响。本提案中列出的实验旨在全面评估抑制回路上的受体特性，抑制回路被证明是精神分裂症病理过程中最脆弱的大脑部分之一。实验将在正常和mk -801处理的动物模型中进行。

DESCRIPTION (provided by applicant): Schizophrenia is probably the most distressing and disabling mental disorder. It affects almost 1% of the human population. Although the pathological processes of this disease is still not clear, remarkable progresses have been made in the past decades to solve this mystery. According to the postmortem studies of the brains of schizophrenia patients, it is now clear that certain inhibitory neurons in the forebrain are selectively damaged. In addition, a group of dissociative anesthetics, such as phencyclidine (PCP, Sernyl, also called 'angel dust') and its related compounds MK-801 and ketamine, can produce a wide range of schizophrenia-like symptoms such as estrangement, thought disorder, hallucination, and psychosis in both surgical patients and health volunteers. These drugs could also cause similar damage of inhibitory interneurons in the forebrain of animal models. Since these drugs are also NMDA receptor antagonists, a hypofunction hypothesis of NMDA receptors and inhibitory interneuron has thus been proposed for the schizophrenia pathological process. This intriguing hypothesis has attracted a great deal of attention, but the direct evidence in support of this hypothesis is still lacking. In this proposal, we hypothesize that the receptor properties of a subpopulation of interneurons in the prefrontal cortex are uniquely organized and these properties make them highly vulnerable to environmental factors that cause schizophrenia. The experiments listed in this proposal are designed to provide a comprehensive assessment of the receptor properties on the inhibitory circuitry which are evidenced as one of the most vulnerable parts of the brain in the schizophrenia pathological process. The experiments will be conducted in both normal and MK-801-treated animal models.