Krembil Family Epigenetics Laboratory, Centre for Addiction and Mental Health, 250 College St, Toronto, ON M5T 1R8, Canada.
Neuropharmacology. 2012 Mar;62(3):1484-503. doi: 10.1016/j.neuropharm.2011.01.030. Epub 2011 Feb 2.
The glutamate neurotransmitter system is one of the major candidate pathways for the pathophysiology of schizophrenia, and increased understanding of the pharmacology, molecular biology and biochemistry of this system may lead to novel treatments. Glutamatergic hypofunction, particularly at the NMDA receptor, has been hypothesized to underlie many of the symptoms of schizophrenia, including psychosis, negative symptoms and cognitive impairment. This review will focus on D-serine, a co-agonist at the NMDA receptor that in combination with glutamate, is required for full activation of this ion channel receptor. Evidence implicating D-serine, NMDA receptors and related molecules, such as D-amino acid oxidase (DAO), G72 and serine racemase (SRR), in the etiology or pathophysiology of schizophrenia is discussed, including knowledge gained from mouse models with altered D-serine pathway genes and from preliminary clinical trials with D-serine itself or compounds modulating the D-serine pathway. Abnormalities in D-serine availability may underlie glutamatergic dysfunction in schizophrenia, and the development of new treatments acting through the D-serine pathway may significantly improve outcomes for many schizophrenia patients.
谷氨酸神经递质系统是精神分裂症病理生理学的主要候选途径之一，对该系统的药理学、分子生物学和生物化学的深入了解可能会带来新的治疗方法。谷氨酸能功能低下，特别是 NMDA 受体，被假设是许多精神分裂症症状的基础，包括精神病、阴性症状和认知障碍。这篇综述将重点介绍 D-丝氨酸，它是 NMDA 受体的协同激动剂，与谷氨酸一起，是充分激活这种离子通道受体所必需的。讨论了 D-丝氨酸、NMDA 受体和相关分子（如 D-氨基酸氧化酶（DAO）、G72 和丝氨酸 racemase（SRR））在精神分裂症的病因或病理生理学中的作用，包括从改变 D-丝氨酸途径基因的小鼠模型中获得的知识，以及从 D-丝氨酸本身或调节 D-丝氨酸途径的化合物的初步临床试验中获得的知识。D-丝氨酸可用性的异常可能是精神分裂症中谷氨酸能功能障碍的基础，通过 D-丝氨酸途径开发新的治疗方法可能会显著改善许多精神分裂症患者的预后。
