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 language | English (US) |
|---|---|
| Pages (from-to) | 15653-15658 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 102 |
| Issue number | 43 |
| DOIs | |
| State | Published - Oct 25 2005 |
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Keywords
- Bipolar disorder
- GABA receptors
- Glutamate transporters
- Major depression
- Suicide
ASJC Scopus subject areas
- Genetics
- General
Cite this
Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. / Choudary, Prabhakara 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.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 43, 25.10.2005, p. 15653-15658.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression
AU - Choudary, Prabhakara V
AU - Molnar, M.
AU - Evans, S. J.
AU - Tomita, H.
AU - Li, J. Z.
AU - Vawter, M. P.
AU - Myers, R. M.
AU - Bunney, W. E.
AU - Akil, H.
AU - Watson, S. J.
AU - Jones, E. G.
PY - 2005/10/25
Y1 - 2005/10/25
N2 - 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.
AB - 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.
KW - Bipolar disorder
KW - GABA receptors
KW - Glutamate transporters
KW - Major depression
KW - Suicide
UR - http://www.scopus.com/inward/record.url?scp=27344456829&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=27344456829&partnerID=8YFLogxK
U2 - 10.1073/pnas.0507901102
DO - 10.1073/pnas.0507901102
M3 - Article
C2 - 16230605
AN - SCOPUS:27344456829
VL - 102
SP - 15653
EP - 15658
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 43
ER -