Repression of Astrocytic Connexins in Cortical and Subcortical Brain Regions and Prefrontal Enrichment of H3K9me3 in Depression and Suicide
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Background: Major depressive disorder has been associated with dysfunctional astrocytic networks. The underlying causes, extent, and consequences of such dysfunctions remain to be characterized. Astrocyte-astrocyte communication occurs principally through gap junction channels primarily formed by connexin 30 and 43 (CX30 and CX43). We previously reported decreased connexin expression in the prefrontal cortex of depressed suicides. In the present study, we investigated whether these changes are mediated by epigenetic regulation, and expanded gene expression quantifications to other cortical and subcortical regions to assess the regional distribution of connexion disruptions in depressed suicides. Methods: The expression of CX30 and CX43 was measured by real-time PCR in samples of neocortex (Brodmann areas 4 and 17), cerebellar cortex, mediodorsal thalamus, and caudate nucleus of 22 depressed suicides and 22 matched sudden-death controls. Chromatin immunoprecipitation was used to measure enrichment levels of the repressive chromatin mark H3K9me3 in the prefrontal cortex. Results: We found a consistent downregulation of connexin genes in all regions examined, except in the cerebellum where an increase in the expression of CX30 was measured and using chromatin immunoprecipitation we observed an enrichment of H3K9me3 for both Cx30 and Cx43 in the prefrontal cortex. Conclusions: Our study shows widespread astrocytic CX gene repression in depressed suicides that is mediated, at least in part, through epigenetic mechanisms. Taken together, these findings support the notion of widespread cerebral astrocytic dysfunction in major depressive disorder.
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Gap junctions that enable communication between astrocytes are formed by the membrane proteins Cx30 and Cx43.
“Gap junctions that enable communication between astrocytes are formed by the membrane proteins Cx30 and Cx43. 163”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [163]
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Regulation of chromatin by histone modifications
Bannister, A. J., & Kouzarides, T. (2011) · Cell Research · doi:10.1038/cr.2011.22 · Cited by 6,012 · see citing works
Glial reduction in the subgenual prefrontal cortex in mood disorders
Öngür, D., Drevets, W. C., & Price, J. L. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.22.13290 · Cited by 1,525 · see citing works
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“To determine a possible mechanism for the strong repression of connexin genes, we examined the PFC, a region canonically implicated in depression (Koenigs and Grafman, 2009) that is strongly associated with the subcortical regions (Mega and Cummings, 1994) examined in this study.”
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- Authors
- Nagy, C., Torres-Platas, S. G., Mechawar, N., & Turecki, G.
- Affiliations
- Douglas Mental Health University Institute (CA)
- Corresponding author
- Mechawar, Naguib
- Turecki, Gustavo
- Venue
- International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-08-11
- Volume
- 20
- Issue
- 1
- Pages
- pyw071
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- PMC
- PMC5737582
- OpenAlex
- W2513929705
- Cited by
- 98
- References
- 5
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 13 · 2023: 11 · 2022: 12 · 2021: 14 · 2020: 10 · 2019: 8 · 2018: 6 · 2017: 7 · 2016: 1 · 2015: 1
- FWCI
- 3.81
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MOP-93775)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- major depressive disorder, suicide, astrocytes, connexin 30, connexin 43, gap junctions, H3K9me3, epigenetic regulation, chromatin repression, prefrontal cortex, cerebellum, mediodorsal thalamus, caudate nucleus, regional gene expression
- MeSH terms
- Connexin 30, Adult, Astrocytes, Brain, Depressive Disorder, Histones, Humans, Male, Suicide, Cohort Studies, Gene Expression, Connexin 43, DNA Methylation, Gray Matter
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