Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; email:
Annu Rev Neurosci. 2015 Jul 8;38:127-49. doi: 10.1146/annurev-neuro-071714-033821. Epub 2015 Apr 9.
Accumulating data, including those from large genetic association studies, indicate that alterations in glutamatergic synapse structure and function represent a common underlying pathology in many symptomatically distinct cognitive disorders. In this review, we discuss evidence from human genetic studies and data from animal models supporting a role for aberrant glutamatergic synapse function in the etiology of intellectual disability (ID), autism spectrum disorder (ASD), and schizophrenia (SCZ), neurodevelopmental disorders that comprise a significant proportion of human cognitive disease and exact a substantial financial and social burden. The varied manifestations of impaired perceptual processing, executive function, social interaction, communication, and/or intellectual ability in ID, ASD, and SCZ appear to emerge from altered neural microstructure, function, and/or wiring rather than gross changes in neuron number or morphology. Here, we review evidence that these disorders may share a common underlying neuropathy: altered excitatory synapse function. We focus on the most promising candidate genes affecting glutamatergic synapse function, highlighting the likely disease-relevant functional consequences of each. We first present a brief overview of glutamatergic synapses and then explore the genetic and phenotypic evidence for altered glutamate signaling in ID, ASD, and SCZ.
越来越多的数据表明，包括来自大型遗传关联研究的数据，谷氨酸能突触结构和功能的改变代表了许多症状明显不同的认知障碍的共同潜在病理学。在这篇综述中，我们讨论了来自人类遗传研究的证据和动物模型的数据，这些证据支持异常谷氨酸能突触功能在智力障碍（ID）、自闭症谱系障碍（ASD）和精神分裂症（SCZ）病因中的作用，这些神经发育障碍构成了人类认知疾病的很大一部分，给社会带来了巨大的经济和社会负担。ID、ASD 和 SCZ 中感知处理、执行功能、社交互动、沟通和/或智力能力受损的各种表现似乎源于神经微结构、功能和/或布线的改变，而不是神经元数量或形态的巨大变化。在这里，我们回顾了这些疾病可能共享共同潜在神经病变的证据：改变的兴奋性突触功能。我们专注于影响谷氨酸能突触功能的最有希望的候选基因，强调每个基因的可能与疾病相关的功能后果。我们首先简要介绍了谷氨酸能突触，然后探讨了 ID、ASD 和 SCZ 中谷氨酸信号改变的遗传和表型证据。
