Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression
Open accessAbstract
Accumulating evidence suggests dysfunction of the gamma-aminobutyric acid (GABA) system in major depressive disorder (MDD). Neuroimaging studies consistently report reductions of cortical GABA in depressed patients. Our post-mortem analyses demonstrate a reduction in the density and size of GABAergic interneurons in the dorsolateral prefrontal cortex (DLPFC) in MDD. The goal of this study was to test whether the level of glutamic acid decarboxylase (GAD), the GABA synthesizing enzyme, will also be reduced in the same cortical region in MDD. Levels of GAD-65 and GAD-67 proteins were investigated by Western blotting in samples from the DLPFC (BA 9) in 13 medication-free subjects with MDD, and 13 psychiatrically healthy controls. The overall amount of GAD-67 was significantly reduced (-34%) in depressed subjects compared to matched controls. Since recent neuroimaging studies have demonstrated that antidepressants modulate GABA levels, additional experiments were performed to examine the levels of GAD in eight depressed subjects treated with antidepressant medications. Levels of GAD-67 were unchanged in these depressed subjects compared to their respective controls (n=8). The overall amounts of GAD-65 were similar in depressed subjects compared to matched controls, regardless of antidepressant medication. Reduced levels of GAD-67, which is localized to somata of GABA neurons, further support our observation of a decreased density of GABAergic neurons in the PFC in depression. It is likely that a decrease in GAD-67 accounts for the reduction in GABA levels revealed by neuroimaging studies. Moreover, our data support previous neuroimaging observations that antidepressant medication normalizes GABA deficits in depression.
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Decreased cortical levels of GABA and specific populations of GABA neurons have been reported in postmortem MDD patient tissues.
“Decreased cortical levels of GABA and specific populations of GABA neurons have been reported in investigations of postmortem MDD patient tissues, 440”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [440]
The Introduction reports reduced density and size of calbindin-positive GABAergic interneurons in postmortem MDD prefrontal cortex. But the paper's own postmortem measurement was of GAD-67 protein, not GABA levels; the cortical GABA reductions it reports came from neuroimaging studies of living patients (Discussion). (LLM, conf=0.88)
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- Authors
- Karolewicz, B., Maciag, D., O'Dwyer, G., Stockmeier, C. A., Feyissa, A. M., & Rajkowska, G.
- Affiliations
- University of Mississippi Medical Center (US)
- Corresponding author
- Karolewicz, Beata
- Venue
- The International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-09-15
- Volume
- 13
- Issue
- 04
- Pages
- 411
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- PMC
- PMC2857696
- OpenAlex
- W2047432718
- Cited by
- 203
- References
- 52
- Citations by year
- 2026: 14 · 2025: 11 · 2024: 17 · 2023: 13 · 2022: 9 · 2021: 17 · 2020: 14 · 2019: 23 · 2018: 10 · 2017: 8 · 2016: 12 · 2015: 12 · 2014: 12 · 2013: 6 · 2012: 12
- FWCI
- 5.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Eli Lilly and Company
- National Institutes of Health (5p20rr017701-10)
- National Institute of Mental Health (R01MH067996, MH67996, MH60451, P50MH060451)
- National Center for Research Resources (P20-RR-017701, RR017701)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- major depressive disorder, glutamic acid decarboxylase 67, GABAergic interneurons, dorsolateral prefrontal cortex, antidepressants, postmortem brain, GABA synthesis
- MeSH terms
- Adult, Aged, Aged, 80 and over, Antidepressive Agents, Major Depressive Disorder, Female, Glutamate Decarboxylase, Humans, Isoenzymes, Male, Middle Aged, Case-Control Studies, Prefrontal Cortex
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