Gap Junction Dysfunction in the Prefrontal Cortex Induces Depressive-Like Behaviors in Rats
Open accessAbstract
Growing evidence has implicated glial anomalies in the pathophysiology of major depression disorder (MDD). Gap junctional communication is a main determinant of astrocytic function. However, it is unclear whether gap junction dysfunction is involved in MDD development. This study investigates changes in the function of astrocyte gap junction occurring in the rat prefrontal cortex (PFC) after chronic unpredictable stress (CUS), a rodent model of depression. Animals exposed to CUS and showing behavioral deficits in sucrose preference test (SPT) and novelty suppressed feeding test (NSFT) exhibited significant decreases in diffusion of gap junction channel-permeable dye and expression of connexin 43 (Cx43), a major component of astrocyte gap junction, and abnormal gap junctional ultrastructure in the PFC. Furthermore, we analyzed the effects of typical antidepressants fluoxetine and duloxetine and glucocorticoid receptor (GR) antagonist mifepristone on CUS-induced gap junctional dysfunction and depressive-like behaviors. The cellular and behavioral alterations induced by CUS were reversed and/or blocked by treatment with typical antidepressants or mifepristone, indicating that the mechanism of their antidepressant action may involve the amelioration of gap junction dysfunction and the cellular changes may be related to GR activation. We then investigated the effects of pharmacological gap junction blockade in the PFC on depressive-like behaviors. The results demonstrate that carbenoxolone (CBX) infusions induced anhedonia in SPT, and anxiety in NSFT, and Cx43 mimetic peptides Gap27 and Gap26 also induced anhedonia, a core symptom of depression. Together, this study supports the hypothesis that gap junction dysfunction contributes to the pathophysiology of depression.
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Chronic treatment with duloxetine increases the expression of connexin 43 in the rat prefrontal cortex, preventing chronic unpredictable stress-induced dysfunction of astrocyte gap junctions and reversing depressive-like behaviors caused by gap junction inhibition.
“Chronic treatment with DXT increases the expression of connexin 43 (Cx43), a crucial component of astrocyte gap junctions, in the rat PFC, preventing chronic unpredictable stress-induced dysfunction of astrocyte gap junctions and reversing the depressive-like behaviors caused by gap junction inhibition. 71”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [71]
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Experimental — accuracy not yet measuredChronic treatment with fluoxetine increases the expression of Cx43 in the rat PFC, prevents dysfunction of astrocytic gap junctions induced by CUS, and reverses depressive-like behaviors caused by gap junction blockade.
“Chronic treatment with fluoxetine has been shown to increase the expression of Cx43 in the rat PFC, which further prevents the dysfunction of astrocytic gap junctions induced by CUS and reverses the depressive-like behaviors caused by gap junction blockade. 71”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [71]
The Discussion reports that chronic fluoxetine increased Cx43 protein in the rat PFC and prevented or reversed CUS-induced astrocytic gap-junction dysfunction. It separately reports that gap-junction blockade induced depressive-like behaviors, but does not say fluoxetine reversed behaviors caused by that blockade. Page numbers are unavailable in our copy. (LLM, conf=0.89)
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- Authors
- Sun, J.-D., Liu, Y., Yuan, Y.-H., Li, J., & Chen, N.-H.
- Affiliations
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Chen, Nai-Hong
- Venue
- Neuropsychopharmacology
- Published
- 2011-12-21
- Volume
- 37
- Issue
- 5
- Pages
- 1305-1320
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3306892
- OpenAlex
- W2060938551
- Cited by
- 258
- References
- 68
- Citations by year
- 2026: 10 · 2025: 25 · 2024: 20 · 2023: 27 · 2022: 20 · 2021: 25 · 2020: 18 · 2019: 23 · 2018: 12 · 2017: 15 · 2016: 16 · 2015: 20 · 2014: 12 · 2013: 10 · 2012: 5
- FWCI
- 3.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Academy of Medical Sciences
- National Natural Science Foundation of China (81073078, 30973887, 2012ZX09301002-004, U832008)
- Chinese Academy of Sciences
- Chinese Academy of Medical Sciences
- Peking Union Medical College
- 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
- astrocytes, prefrontal cortex, major depressive disorder, chronic unpredictable mild stress, connexin 43, glucocorticoid receptor, mifepristone, fluoxetine, duloxetine, carbenoxolone, Gap27, anhedonia, anxiety, antidepressant mechanism, glial dysfunction
- MeSH terms
- Duloxetine Hydrochloride, Analysis of Variance, Animals, Carbenoxolone, Disease Models, Animal, Electroshock, Exploratory Behavior, Fluoxetine, Food Deprivation, Food Preferences, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Hormone Antagonists, Inhibition, Psychological, Isoquinolines, Male, Restraint, Physical, RNA, Messenger, Social Isolation, Stress, Psychological, Sucrose, Sweetening Agents, Swimming, Thiophenes, Mifepristone, Rats, Sprague-Dawley, Selective Serotonin Reuptake Inhibitors, Prefrontal Cortex, Gap Junctions, Connexin 43, Microscopy, Electron, Transmission, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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