Molecular pathways of the kynurenine system in the neuroimmunology and psychophysiology of schizophrenia.

摘要 几项大型流行病学研究发现，持续感染 (e.g CMV、HSV 1、弓形虫）和认知指数（如 反应时间或数字广度测试。人们对感染的可能作用也越来越感兴趣 在精神分裂症的认知特征（SCZ）中。然而，需要测试特定的 将持续感染和失调的免疫机制联系起来的生物机制， SCZ相关的阴性症状和认知缺陷。细胞因子干扰素γ（IFNg）， 由外周免疫细胞以及神经胶质细胞产生，在控制持续性 嗜神经病原体和介导免疫和神经之间的通信 系统. IFNg的主要机制是色氨酸降解沿着 犬尿氨酸（KYN）途径通过酶控制的一系列步骤。这使得 KYN和犬尿烯酸（KYNA）水平升高。KYNA反过来又在两个关键点上充当拮抗剂 神经递质受体：谷氨酸受体的N-甲基-D-天冬氨酸（NMDA）亚型 和α-7烟碱乙酰胆碱（α 7 nACh）受体。此外，一个新的 KYNA的受体G蛋白连接受体35（GPR 35）尚未被发现。 研究其对精神分裂症相关认知缺陷的贡献。该补助金的目的是 是为了检查特定的神经免疫机制，这些机制是与 感染和某些细胞受体在认知和阴性症状 精神分裂症我们专注于明确的心理生理指标和认知测试， 检查IFNg激活，以及KYN相关配体和GPR 35受体的不平衡， 精神分裂症的认知缺陷内表型

ABSRACT Several large epidemiological studies have found an association between persistent infections (e.g CMV, HSV1, Toxoplasma gondii) and poor performance on indices of cognition such as reaction time or digit span tests. There is also growing interest in the possible role of infections in the cognitive profile of schizophrenia (SCZ). However, there is a need to test specific biological mechanisms that link persistent infections and dysregulated immune mechanisms to SCZ-related negative symptoms and cognitive deficits. The cytokine interferon gamma (IFNg), produced by peripheral immune cells as well as glia, plays a crucial role in controlling persistent neurotropic pathogens and in mediating the communication between the immune and nervous systems. A primary mechanism of IFNg is the shunting tryptophan degradation along the kynurenine (KYN) pathway through an enzyme-controlled series of steps. This causes the elevation KYN and kynurenic acid (KYNA) levels. KYNA in turn acts as an antagonist at two key neurotransmitter receptors: the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor and the alpha-7 nicotinic acetylcholine (a7nACh) receptor. Moreover, the effect of a newly discovered receptor for KYNA, G-protein linked receptor 35 (GPR35), has not yet been investigated for its contribution to schizophrenia-related cognitive deficits. The aims of this grant are to examine specific neuroimmune mechanisms that underlie the apparent association of infections and certain cellular receptors in the cognitive and negative symptoms of schizophrenia. We focus on well-defined psychophysiological indices and cognitive tests to examine IFNg activation, and an imbalance in the KYN-related ligands and GPR35 receptors in the cognitive deficit endophenotype of schizophrenia.