ArticleProceedings of the National Academy of Sciences of the United States of America2024
The role of astrocytes in depression, its prevention, and treatment by targeting astroglial gliotransmitter release.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Anterior Cingulate Cortex Astrocytes Regulate Chronic Itch and Comorbid Negative Emotional Disorders in Mice.CNS neuroscience & therapeutics · 2026Article
- Astrocytic connexin 43 hemichannel dysregulation drives prefrontal circuit dysfunction and schizophrenia-like behaviors.Molecular psychiatry · 2026Article
- Life Cycle and Circadian Rhythms in Central Resident Immunity and Neuropsychiatric Pathology.Neuroscience bulletin · 2026Review
- Cerebellar astrocytic alterations in depression.Translational psychiatry · 2026Article
- Neuroinflammation and treatment resistance in major depressive disorder.Frontiers in pharmacology · 2026Review
- From metabolism to mood regulation: astrocytes as a driver of depression.Frontiers in cellular neuroscience · 2026Review
- The Fractalkine (FKN/CX3CL1) Pathway in Depression: A Critical Review of Its Role in Neuroinflammation and Therapeutic Potential.Neuropsychiatric disease and treatment · 2026Review
- Chronic Stress and Astrocyte Dysfunction in Depression: Molecular Mechanisms and Gene Expression Changes.Antioxidants (Basel, Switzerland) · 2025Review
- Untargeted metabolomics revealed that quercetin improves rat renal metabolic disorders induced by chronic unpredictable mild stress.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- NLRP3 Inflammasome in Stress-Related Neuropsychiatric Disorders: Mechanisms of Neuron-Microglia-Astrocyte Crosstalk, HPA Axis Dysregulation, and Therapeutic Perspective.Biomolecules · 2025Review
- Connexin43 and Its Regulation of Astrocyte Gap Junction Function: Influencing Depression Progression by Mediating Electrical and Chemical Signals.CNS neuroscience & therapeutics · 2025Review
- When the Stars Misfire: Astrocytic Dysfunctions in Major Depressive Disorder.Neurochemical research · 2025Review
- Research progress of connexins in epileptogensis.Acta epileptologica · 2025Review
- Benchmarking macaque brain gene expression for horizontal and vertical translation.Science advances · 2025Article
Corrections and comments
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Authors and funding
26 authors.
Funding
Abstract
The role of ventral hippocampus (vHipp) astroglial gliotransmission in depression was studied using chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) rodent models. CRS increased Cx43 hemichannel activity and extracellular glutamate levels in the vHipp and blocking astroglial Cx43 hemichannel-dependent gliotransmission during CRS prevented the development of depression and glutamate buildup. Moreover, the acute blockade of Cx43 hemichannels induced antidepressant effects in rats previously subjected to CRS or CUMS. This antidepressant effect was prevented by coinjection of glutamate and D-serine. Furthermore, Cx43 hemichannel blockade decreased postsynaptic NMDAR currents in vHipp slices in a glutamate and D-serine-dependent manner. Notably, chronic microinfusion of glutamate and D-serine, L-serine, or the NMDAR agonist NMDA, into the vHipp induced depressive-like symptoms in nonstressed rats. We also identified a small molecule, cacotheline, which blocks Cx43 hemichannels and its systemic administration induced rapid antidepressant effects, preventing stress-induced increases in astroglial Cx43 hemichannel activity and extracellular glutamate in the vHipp, without sedative or locomotor side effects. In conclusion, chronic stress increases Cx43 hemichannel-dependent release of glutamate and D-/L-serine from astrocytes in the vHipp, overactivating postsynaptic NMDARs and triggering depressive-like symptoms. This study highlights the critical role of astroglial gliotransmitter release in chronic stress-induced depression and suggests it can be used as a target for the prevention and treatment of depression.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.