Glutamate synapses in human cognitive disorders

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.

Keywords: autism; excitatory; intellectual disability; neurodevelopmental; plasticity; schizophrenia.

Publication types

  • Review

MeSH terms

  • Animals
  • Autism Spectrum Disorder / genetics
  • Autism Spectrum Disorder / physiopathology
  • Cognition Disorders / genetics*
  • Cognition Disorders / physiopathology*
  • Genetic Predisposition to Disease / genetics*
  • Glutamic Acid / physiology*
  • Humans
  • Intellectual Disability / genetics
  • Intellectual Disability / physiopathology
  • Models, Neurological
  • Schizophrenia / genetics
  • Schizophrenia / physiopathology
  • Synapses / genetics*
  • Synapses / physiology*


  • Glutamic Acid