The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies

Ann N Y Acad Sci. 2015 Mar;1338(1):38-57. doi: 10.1111/nyas.12547. Epub 2014 Oct 14.


A number of studies have indicated that antagonists of the N-methyl-d-aspartate subtypes of glutamate receptors can cause schizophrenia-like symptoms in healthy individuals and exacerbate symptoms in individuals with schizophrenia. These findings have led to the glutamate hypothesis of schizophrenia. Here we review the evidence for this hypothesis in postmortem studies of brain tissue from individuals affected by schizophrenia, summarizing studies of glutamate neuron morphology, of expression of glutamate receptors and transporters, and of the synthesizing and metabolizing enzymes for glutamate and its co-agonists. We found consistent evidence of morphological alterations of dendrites of glutamatergic neurons in the cerebral cortex of subjects with schizophrenia and of reduced levels of the axon bouton marker synaptophysin. There were no consistent alterations of mRNA expression of glutamate receptors, although there has been limited study of the corresponding proteins. Studies of the glutamate metabolic pathway have been limited, although there is some evidence that excitatory amino acid transporter-2, glutamine synthetase, and glutaminase have altered expression in schizophrenia. Future studies would benefit from additional direct examination of glutamatergic proteins. Further advances, such as selective testing of synaptic microdomains, cortical layers, and neuronal subtypes, may also be required to elucidate the nature of glutamate signaling impairments in schizophrenia.

Keywords: EAAT; brain tissue; glutamate receptors; glutamatergic neurons; schizophrenia.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Brain / metabolism*
  • Female
  • Glutamic Acid / metabolism*
  • Humans
  • Male
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Glutamate / genetics
  • Receptors, Glutamate / metabolism
  • Schizophrenia / metabolism*


  • RNA, Messenger
  • Receptors, Glutamate
  • Glutamic Acid