Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, PO Box 21247, Baltimore, MD 21228, USA.
Schizophr Bull. 2010 Mar;36(2):211-8. doi: 10.1093/schbul/sbq002. Epub 2010 Feb 10.
The brain concentration of kynurenic acid (KYNA), a metabolite of the kynurenine pathway of tryptophan degradation and antagonist at both the glycine coagonist site of the N-methyl-D-aspartic acid receptor (NMDAR) and the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), is elevated in the prefrontal cortex (PFC) of individuals with schizophrenia. This increase may be clinically relevant because hypofunction of both the NMDAR and the alpha7nAChR are implicated in the pathophysiology, and especially in the cognitive deficits associated with the disease. In rat PFC, fluctuations in endogenous KYNA levels bidirectionally modulate extracellular levels of 3 neurotransmitters closely related to cognitive function (glutamate, dopamine, and acetylcholine). Moreover, behavioral studies in rats have demonstrated a causal link between increased cortical KYNA levels and neurocognitive deficits, including impairment in spatial working memory, contextual learning, sensory gating, and prepulse inhibition of the startle reflex. In recent human postmortem studies, impairments in gene expression and activity of kynurenine pathway enzymes were found in cortical areas of individuals with schizophrenia. Additional studies have revealed an interesting association between a sequence variant in the gene of one of these enzymes, kynurenine 3-monooxygenase, and neurocognitive deficits seen in patients. The emerging, remarkable confluence of data from humans and animals suggests an opportunity for developing a rational pharmacology by targeting cortical kynurenine pathway metabolism for cognition enhancement in schizophrenia and beyond.
色氨酸降解的犬尿酸（KYNA）是一种代谢产物，作为 N-甲基-D-天冬氨酸受体（NMDAR）和α7 烟碱型乙酰胆碱受体（α7nAChR）的甘氨酸共激动剂位点的拮抗剂，其在精神分裂症患者的前额叶皮层（PFC）中的浓度升高。这种增加可能具有临床相关性，因为 NMDAR 和 α7nAChR 的功能低下都与疾病的病理生理学，尤其是与疾病相关的认知缺陷有关。在大鼠 PFC 中，内源性 KYNA 水平的波动双向调节与认知功能密切相关的 3 种神经递质（谷氨酸、多巴胺和乙酰胆碱）的细胞外水平。此外，大鼠的行为研究表明，皮质 KYNA 水平升高与神经认知缺陷之间存在因果关系，包括空间工作记忆、情境学习、感觉门控和惊吓反射的起始抑制受损。在最近的人类尸检研究中，发现精神分裂症患者的皮质区域中犬尿氨酸途径酶的基因表达和活性受损。其他研究还揭示了这些酶之一，犬尿氨酸 3-单加氧酶的基因中的一个序列变异与患者中观察到的神经认知缺陷之间存在有趣的关联。来自人类和动物的数据的新兴显著融合表明，有机会通过针对皮质犬尿氨酸途径代谢来开发一种合理的药理学，以增强精神分裂症和其他疾病的认知。
