{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T21:39:36Z","timestamp":1787693976860,"version":"build-2784847793"},"reference-count":44,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>5q-associated Spinal Muscular Atrophy (SMA) is a hereditary neuromuscular disorder caused by mutations in the survival of motor neuron 1 (SMN1) gene, leading to progressive muscle weakness, and atrophy. While traditionally viewed as a motor neuron (MN)-specific disease, emerging evidence highlights the critical role of astrocytes, particularly in regulating extracellular glutamate and mitigating MN toxicity. Here, we investigated astrocytic gap junctions with a focus on connexin 43 (Cx43). Using in vivo and in vitro approaches\u2014including a late-onset SMA mouse model, human-derived astrocytes, and murine astrocyte cultures\u2014we analyzed Cx43 expression and localization via genetic modification, immunostaining, Western blotting, and quantitative PCR. Functional consequences were assessed using ex vivo spinal cord slice cultures, Ca2+-imaging, and glutamate release assays. We found significant Cx43 upregulation in late-onset SMA mice, as well as in SMN-deficient murine and human-derived astrocytes. Increased Cx43 expression correlated with elevated astrocytic glutamate release and MN toxicity. Ca2+-imaging indicated Cx43-dependent mechanisms underlying this enhanced release. Pharmacological Cx43 inhibition with Gap27 reduced glutamate release and MN Ca2+ responses. These findings identify astrocytic Cx43 as a contributor to glutamate-mediated MN toxicity in late-onset SMA and support growing recognition of non-neuronal mechanisms in SMA pathology.<\/jats:p>","DOI":"10.3390\/cells14231852","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T10:46:18Z","timestamp":1764067578000},"page":"1852","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting Astrocytic Connexin 43 Mitigates Glutamate-Driven Motor Neuron Stress in Late-Onset Spinal Muscular Atrophy"],"prefix":"10.3390","volume":"14","author":[{"given":"Schahin","family":"Salmanian","sequence":"first","affiliation":[{"name":"Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda-Isabell","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5696-3459","authenticated-orcid":false,"given":"Kai Christine","family":"Liebig","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Hezel","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2833-0928","authenticated-orcid":false,"given":"Andreas","family":"Roos","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Schara-Schmidt","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1650-8875","authenticated-orcid":false,"given":"Christoph","family":"Kleinschnitz","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3449-9829","authenticated-orcid":false,"given":"Markus","family":"Leo","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3631-3450","authenticated-orcid":false,"given":"Tim","family":"Hagenacker","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1006\/nbdi.1996.0010","article-title":"The Neurobiology of Childhood Spinal Muscular Atrophy","volume":"3","author":"Crawford","year":"1996","journal-title":"Neurobiol. 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