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

被引:498
作者
Choudary, PV
Molnar, M
Evans, SJ
Tomita, H
Li, JZ
Vawter, MP
Myers, RM
Bunney, WE
Akil, H
Watson, SJ
Jones, EG
机构
[1] Univ Calif Davis, Ctr Neurosci, Davis, CA 95616 USA
[2] Univ Calif Davis, Dept Psychiat & Behav Sci, Davis, CA 95616 USA
[3] Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA
[4] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92697 USA
[5] Stanford Univ, Stanford Human Genome Ctr, Stanford, CA 94305 USA
[6] Stanford Univ, Dept Genet, Stanford, CA 94305 USA
关键词
bipolar disorder; GABA(A) receptors; glutamate transporters; major depression; suicide;
D O I
10.1073/pnas.0507901102
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 SLC1A2 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 GABA(A) receptor subunits, of which GABA(A)alpha 1 and GABA(A)beta 3 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.
引用
收藏
页码:15653 / 15658
页数:6
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