Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression

Prabhakara V Choudary, M. Molnar, S. J. Evans, H. Tomita, J. Z. Li, M. P. Vawter, R. M. Myers, W. E. Bunney, H. Akil, S. J. Watson, E. G. Jones

Research output: Contribution to journalArticle

432 Scopus citations

Abstract

Abnormalities in L-glutamic acid (glutamate) and GABA signal transmission have been postulated to play a role in depression, but little is known about the underlying molecular determinants and neural mechanisms. Microarray analysis of specific areas of cerebral cortex from individuals who had suffered from major depressive disorder demonstrated significant down-regulation of SLCIA2 and SLC1A3, two key members of the glutamate/neutral amino acid transporter protein family, SLC1. Similarly, expression of L-glutamate-ammonia ligase, the enzyme that converts glutamate to nontoxic glutamine was significantly decreased. Together, these changes could elevate levels of extracellular glutamate considerably, which is potentially neurotoxic and can affect the efficiency of glutamate signaling. The astroglial distribution of the two glutamate transporters and L-glutamate-ammonia ligase strongly links glia to the pathophysiology of depression and challenges the conventional notion that depression is solely a neuronal disorder. The same cortical areas displayed concomitant up-regulation of several glutamate and GABAA receptor subunits, of which GABAAα1 and GABAAβ3 showed selectivity for individuals who had died by suicide, indicating their potential utility as biomarkers of suicidality. These findings point to previously undiscovered molecular underpinnings of the pathophysiology of major depression and offer potentially new pharmacological targets for treating depression.

Original languageEnglish (US)
Pages (from-to)15653-15658
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number43
DOIs
StatePublished - Oct 25 2005

    Fingerprint

Keywords

  • Bipolar disorder
  • GABA receptors
  • Glutamate transporters
  • Major depression
  • Suicide

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Choudary, P. V., Molnar, M., Evans, S. J., Tomita, H., Li, J. Z., Vawter, M. P., Myers, R. M., Bunney, W. E., Akil, H., Watson, S. J., & Jones, E. G. (2005). Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proceedings of the National Academy of Sciences of the United States of America, 102(43), 15653-15658. https://doi.org/10.1073/pnas.0507901102