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

抽奖 几项大型流行病学研究发现，持续性感染与 (如巨细胞病毒、单纯疱疹病毒1型、弓形虫)和认知指标表现不佳，如 反应时或数字广度测试。人们对感染的可能作用也越来越感兴趣。 在精神分裂症(SCZ)的认知概况中。然而，需要测试特定的 将持续性感染和失调的免疫机制联系起来的生物机制 与SCZ相关的阴性症状和认知缺陷。细胞因子干扰素-γ(IFNG)， 由外周免疫细胞和神经胶质细胞产生，在控制持久性方面起着关键作用 嗜神经性病原体及其在调节免疫和神经之间的通讯中的作用 系统。IFNG的一个主要机制是色氨酸沿 犬尿氨酸(KYN)途径通过一系列酶控制的步骤。这会导致 升高KYN和KYNA水平。Kyna反过来在两个键上扮演对手的角色 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烟碱型乙酰胆碱(A7nACh)受体。此外，一项新的 已发现的KYNA受体G-蛋白连接受体35(GPR35)尚未被 因其对精神分裂症相关认知缺陷的贡献而接受调查。这笔赠款的目的是 是为了检查特定的神经免疫机制，这些机制是明显的 认知和阴性症状中的感染和某些细胞受体 精神分裂症。我们专注于定义明确的心理生理指标和认知测试，以 检测IFNG的激活，以及KYN相关配体和GPR35受体的失衡 精神分裂症患者的认知缺陷表型。

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.