Astrocyte Pathology in Major Depressive Disorder: Insights from Human Postmortem Brain Tissue
Open accessAbstract
The present paper reviews astrocyte pathology in major depressive disorder (MDD) and proposes that reductions in astrocytes and related markers are key features in the pathology of MDD. Astrocytes are the most numerous and versatile of all types of glial cells. They are crucial to the neuronal microenvironment by regulating glucose metabolism, neurotransmitter uptake (particularly for glutamate), synaptic development and maturation and the blood brain barrier. Pathology of astrocytes has been consistently noted in MDD as well as in rodent models of depressive-like behavior. This review summarizes evidence from human postmortem tissue showing alterations in the expression of protein and mRNA for astrocyte markers such as glial fibrillary acidic protein (GFAP), gap junction proteins (connexin 40 and 43), the water channel aquaporin-4 (AQP4), a calcium-binding protein S100B and glutamatergic markers including the excitatory amino acid transporters 1 and 2 (EAAT1, EAAT2) and glutamine synthetase. Moreover, preclinical studies are presented that demonstrate the involvement of GFAP and astrocytes in animal models of stress and depressive-like behavior and the influence of different classes of antidepressant medications on astrocytes. In light of the various astrocyte deficits noted in MDD, astrocytes may be novel targets for the action of antidepressant medications. Possible functional consequences of altered expression of astrocytic markers in MDD are also discussed. Finally, the unique pattern of cell pathology in MDD, characterized by prominent reductions in the density of astrocytes and in the expression of their markers without obvious neuronal loss, is contrasted with that found in other neuropsychiatric and neurodegenerative disorders.
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In patients with MDD, levels of connexins, glutamine synthase, glutamate transporter-1, and aquaporin-4 are reduced.
“and the levels of connexins, 21 glutamine synthase (GS), glutamate transporter-1 (GLT-1), 21 , 22 and aquaporin-4 (AQP4) 23 are reduced in patients with MDD.”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [23]
Enhanced glutamatergic NMDA-mediated transmission may improve memory consolidation but in excess may be neurotoxic.
“Enhanced glutamatergic NMDA-mediated transmission may improve memory consolidation (136) but in excess may be neurotoxic (137).”
From A brain-centric model of suicidal behavior (2020) · cites this paper as [137]
Suicide risk-related neuron deficits may be attributed to toxic effects of excessive allostatic load due to glucocorticoids and abnormal stress response.
“These suicide risk-related neuron deficits may also be attributed to toxic effects of the excessive allostatic load due to glucocorticoids and abnormal stress response (137).”
From A brain-centric model of suicidal behavior (2020) · cites this paper as [137]
Elevated glucocorticoids may result in loss of astrocytes and glutamate transporters, leading to pathological accumulation of glutamate and subsequent loss of neuronal density.
“Elevated glucocorticoids may result in loss of astrocytes and glutamate transporters. This, in turn, leads to a pathological accumulation of glutamate, with subsequent loss of neuronal density (137).”
From A brain-centric model of suicidal behavior (2020) · cites this paper as [137]
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References 208 · Cited by 603
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- Authors
- Rajkowska, G., & Stockmeier, C.
- Affiliations
- University of Mississippi Medical Center (US)
- ORCID
- Stockmeier, Craig
- Venue
- Current Drug Targets
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2013-09-01
- Volume
- 14
- Issue
- 11
- Pages
- 1225-1236
- ISSN
- 1389-4501 (ISSN-L)
- PMC
- PMC3799810
- OpenAlex
- W2059150405
- Cited by
- 603
- References
- 208
- Citations by year
- 2026: 40 · 2025: 59 · 2024: 42 · 2023: 49 · 2022: 51 · 2021: 87 · 2020: 44 · 2019: 44 · 2018: 37 · 2017: 31 · 2016: 44 · 2015: 34 · 2014: 30 · 2013: 11
- FWCI
- 29.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Current Drug Targets (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5p20rr017701-10)
- National Institute of General Medical Sciences (P30GM103328)
- National Center for Research Resources (P20-RR-017701, 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 › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- major depressive disorder, astrocytes, glial fibrillary acidic protein, connexin 40, connexin 43, aquaporin-4, S100B, glutamate transporters, glutamine synthetase, glutamate, blood-brain barrier, stress, antidepressants, astrocyte-targeted therapy, postmortem brain
- MeSH terms
- Astrocytes, Brain, Depressive Disorder, Major, Major Depressive Disorder, Glial Fibrillary Acidic Protein, Humans, Biomarkers, Connexins, Neurotransmitter Agents, Aquaporin 4
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