Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects
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Major depressive disorder (MDD) has been linked to changes in function and activity of the hippocampus, one of the central limbic regions involved in regulation of emotions and mood. The exact cellular and molecular mechanisms underlying hippocampal plasticity in response to stress are yet to be fully characterized. In this study, we examined the genetic profile of micro-dissected subfields of post-mortem hippocampus from subjects diagnosed with MDD and comparison subjects matched for sex, race and age. Gene expression profiles of the dentate gyrus and CA1 were assessed by 48K human HEEBO whole genome microarrays and a subgroup of identified genes was confirmed by real-time polymerase chain reaction (qPCR). Pathway analysis revealed altered expression of several gene families, including cytoskeletal proteins involved in rearrangement of neuronal processes. Based on this and evidence of hippocampal neuronal atrophy in MDD, we focused on the expression of cytoskeletal, synaptic and glutamate receptor genes. Our findings demonstrate significant dysregulation of synaptic function/structure related genes SNAP25, DLG2 (SAP93), and MAP1A, and 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptor subunit genes GLUR1 and GLUR3. Several of these human target genes were similarly dysregulated in a rat model of chronic unpredictable stress and the effects reversed by antidepressant treatment. Together, these studies provide new evidence that disruption of synaptic and glutamatergic signalling pathways contribute to the pathophysiology underlying MDD and provide interesting targets for novel therapeutic interventions.
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Deficient glutamate clearance reported in major depressive disorder may be due to downregulation of high-affinity glutamate transporters expressed specifically in glia, but not neurons, in human hippocampus.
“Deficient glutamate clearance, reported in MDD, may be due to downregulation of high affinity glutamate transporters, expressed specifically in glia, but not neurons, in human hippocampus 165.”
From Dysregulation of adult hippocampal neuroplasticity in major depression: Pathogenesis and therapeutic implications (2022) · cites this paper as [165]
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- Authors
- Duric, V., Banasr, M., Stockmeier, C. A., Simen, A. A., Newton, S. S., Overholser, J. C., Jurjus, G. J., Dieter, L., & Duman, R. S.
- Affiliations
- Department of Psychiatry, Yale University, New Haven, CT, USA
- Yale University (US)
- University of Mississippi Medical Center (US)
- Case Western Reserve University (US)
- Louis Stokes Cleveland VA Medical Center (US)
- Corresponding author
- Duman, Ronald S.
- ORCID
- Venue
- International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-02-01
- Volume
- 16
- Issue
- 1
- Pages
- 69-82
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- PMC
- PMC3414647
- OpenAlex
- W2026813655
- Cited by
- 304
- References
- 83
- Citations by year
- 2026: 17 · 2025: 21 · 2024: 17 · 2023: 25 · 2022: 32 · 2021: 35 · 2020: 32 · 2019: 14 · 2018: 12 · 2017: 19 · 2016: 27 · 2015: 19 · 2014: 16 · 2013: 7 · 2012: 10
- FWCI
- 12.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5p20rr017701-10)
- U.S. Public Health Service (MH45481)
- National Institute of Mental Health (R01MH067996, MH67996, 2P01 MH25642, MH-45481, R37MH045481, P01MH025642, R01MH045481)
- National Institute of General Medical Sciences (P30GM103328)
- National Center for Research Resources (P20-RR-017701, P20 RR 17701)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- major depressive disorder, hippocampus, gene expression, synapses, glutamate receptors, cytoskeletal proteins, dentate gyrus, CA1, SNAP-25, DLG2, MAP1A, GluR1, GluR3, chronic unpredictable mild stress, antidepressant treatment, hippocampal plasticity, glutamatergic signalling
- MeSH terms
- Adult, Aged, Aged, 80 and over, Animals, Depressive Disorder, Major, Major Depressive Disorder, Female, Gene Expression Regulation, Hippocampus, Humans, Male, Microtubule-Associated Proteins, Middle Aged, Nerve Tissue Proteins, Synapses, Rats, Sprague-Dawley, Receptors, Glutamate, Receptors, AMPA, Tumor Suppressor Proteins, Synaptosomal-Associated Protein 25, Rats, Guanylate Kinases
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