{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T23:31:08Z","timestamp":1785367868074,"version":"3.55.0"},"reference-count":246,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>\n                    Experience-dependent brain circuit optimization choreographed by environmental sensory input activity involves synapse formation, pruning, and remodeling to sculpt appropriate connectivity. The serotonin (5-HT) neuromodulator acts as a core regulator of this circuit plasticity. Classically, serotonergic control has been understood solely through neuronal mechanisms, however new evidence reveals glial 5-HT signaling roles. This review focuses on recent studies in\n                    <jats:italic>Drosophila<\/jats:italic>\n                    with reference to foundational mammalian work to discuss 5-HT functions in both neurons and glia, particularly experience-dependent extracellular matrix remodeling, glial infiltration, and synapse elimination in early-life critical periods. Disruption of serotonergic regulation is proposed to contribute to a spectrum of neurodevelopmental disorders, including Fragile X syndrome, in which failure to prune and persistence of immature connectivity cause severe life-long behavioral impairments. Recent discoveries further reveal targeted induction of glial serotonergic signaling can re-open \u201ccritical period-like\u201d synapse pruning at maturity. Enabling large-scale connectivity changes has broad potential therapeutic applications for disease, injury, trauma, and cognitive dysfunction. A key advance is the emerging evidence that glia\u2014not just neurons\u2014are serotonergic mediators of synaptic remodeling: glial 5-HT biosynthesis, 5-HT\n                    <jats:sub>2A<\/jats:sub>\n                    receptor activation, and matrix metalloprotease-mediated function together allow access for experience-driven synapse elimination. We propose glia-to-glia class serotonergic signaling\u2014linking sensory experience to synapse pruning\u2014may represent a conserved plasticity gating mechanism that determines whether circuitry is permissive or resistant to synaptic connectivity modification. Harnessing glial class-specific serotonergic control of experience-dependent brain circuit remodeling may enable new targeted therapies to correct brain function while avoiding the negative side effects of global serotonin elevation.\n                  <\/jats:p>","DOI":"10.3389\/fnins.2026.1782246","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:03:51Z","timestamp":1775801031000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Partners in plasticity: serotonergic glial interactions in brain circuit remodeling"],"prefix":"10.3389","volume":"20","author":[{"given":"Vanessa Kay","family":"Miller","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Vanderbilt University and Medical Center","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kendal","family":"Broadie","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Vanderbilt University and Medical Center","place":["Nashville, TN, United States"]},{"name":"Department of Cell and Developmental Biology, Vanderbilt University and Medical Center","place":["Nashville, TN, United States"]},{"name":"Department of Pharmacology, Vanderbilt University and Medical Center","place":["Nashville, TN, United States"]},{"name":"Kennedy Center for Research on Human Development, Vanderbilt University and Medical Center","place":["Nashville, TN, United States"]},{"name":"Vanderbilt Brain Institute, Vanderbilt University and Medical Center","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1093\/cercor\/bhaa285","article-title":"Serotonergic modulation of spontaneous and evoked transmitter release in layer II pyramidal cells of rat somatosensory cortex","volume":"31","author":"Agahari","year":"2021","journal-title":"Cereb. 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