GLUTAMATE AND PREFRONTAL CORTEX FUNCTION

大量的证据表明，在精神分裂症的病理生理学中，前额叶皮质功能不正常。虽然许多研究结果描述了单胺能和胆碱能投射到前额皮质的认知功能中与该区域相关的作用，但最普遍的前额皮质传入事件，即那些以谷氨酸为神经递质的投射，在记忆、注意力和前额皮质的其他联想功能中的参与程度尚未得到很好的表征。考虑到最近的一些研究结果提示精神分裂症中存在谷氨酸能异常，因此有必要更多地了解谷氨酸受体在与精神分裂症症状相关的认知功能中的作用。该研究在独立科学家奖（K02）的申请中提出，涉及谷氨酸受体在调节与精神分裂症病理生理相关的前额皮质联想功能中的作用。该奖项将允许申请人为上述研究目标投入最大的努力，这需要接受适当的培训，以便在她的实验室中建立与精神分裂症相关的认知功能障碍的不同方面直接相关的行为范例，并类似于精神分裂症患者表现出损害的临床测试。考虑到目前的精神分裂症治疗模式，即使用抗多巴胺能药物治疗，并不能有效治疗与这种疾病相关的认知缺陷，了解前额叶皮质联想功能的神经化学基础将有助于开发新的精神分裂症药物治疗策略。

A plethora of evidence has implicated the improper functioning of the prefrontal cortex in the pathophysiology of schizophrenia. While numerous findings have described a role for monoaminergic and cholinergic projections to the prefrontal cortex in the cognitive functions associated with this region, the extent of the involvement of the most prevalent prefrontal cortex afferents, namely those projections that contain glutamate as their neurotransmitter, in mnemonic, attentional, and other associative functions of the prefrontal cortex has not been well characterized. Considering that a number of recent findings are suggestive of glutamatergic abnormalities in schizophrenia, it is imperative that more be learned about the role of glutamate receptors in cognitive functions that are relevant to schizophrenic symptomatology. The research proposed in this request for an Independent Scientist Award (K02) involves characterizing the contribution of glutamate receptors in regulating those associative functions of the prefrontal cortex that are relevant to the pathophysiology of schizophrenia. This award will allow the applicant to devote maximal effort to the above research objectives which entails receiving appropriate training in order to establish in her laboratory behavioral paradigms that have direct relevance to different aspects of the cognitive dysfunctions associated with schizophrenia and that are analogous to clinical tests at which patients with schizophrenia show an impairment. Considering that the present mode of therapy for schizophrenia, i.e., treatment with antidopaminergic drugs, does not effectively treat cognitive deficits associated with this disorder, an understanding of the neurochemical basis of associative functions of the prefrontal cortex will help in the development of novel pharmacotherapeutic strategies for the treatment of schizophrenia.