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Here we employed pharmacological, genetic, functional imaging and optogenetic-stimulation approaches in zebrafish to assess activity-regulated myelination in vivo. Pharmacological inhibition and activation of metabotropic glutamate receptor 5 (mGluR5) impaired and promoted myelin sheath elongation, respectively, during development, without otherwise affecting the oligodendrocyte lineage. Correspondingly, mGluR5 loss-of-function mutants exhibit impaired myelin growth, while oligodendrocyte-specific mGluR5 gain of function promoted sheath elongation. Functional imaging and optogenetic-stimulation studies revealed that mGluR5 mediates activity-driven high-amplitude Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transients in myelin. Furthermore, we found that long-term stimulation of neuronal activity drives myelin sheath elongation in an mGluR5-dependent manner. Together these data identify mGluR5 as a mediator of the influence of neuronal activity on myelination by oligodendrocytes in vivo, opening up opportunities to assess the functional relevance of activity-regulated myelination.\n                  <\/jats:p>","DOI":"10.1038\/s41593-025-01956-9","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T05:02:28Z","timestamp":1747198948000},"page":"1213-1225","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Activity-driven myelin sheath growth is mediated by mGluR5"],"prefix":"10.1038","volume":"28","author":[{"given":"Philipp N.","family":"Braaker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuelong","family":"Mi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0413-2820","authenticated-orcid":false,"given":"Daniel","family":"Soong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0450-5300","authenticated-orcid":false,"given":"Jenea M.","family":"Bin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katy","family":"Marshall-Phelps","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Bradley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Benito-Kwiecinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donia","family":"Arafa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Richmond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Keatinge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6743-7413","authenticated-orcid":false,"given":"Guoqiang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3563-5463","authenticated-orcid":false,"given":"Rafael G.","family":"Almeida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1166-4454","authenticated-orcid":false,"given":"David A.","family":"Lyons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,14]]},"reference":[{"key":"1956_CR1","doi-asserted-by":"publisher","first-page":"10023","DOI":"10.1523\/JNEUROSCI.3185-16.2017","volume":"37","author":"RG Almeida","year":"2017","unstructured":"Almeida, R. G. & Lyons, D. A. On myelinated axon plasticity and neuronal circuit formation and function. J. Neurosci. 37, 10023\u201310034 (2017).","journal-title":"J. Neurosci."},{"key":"1956_CR2","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1038\/s41583-023-00744-3","volume":"24","author":"KR Taylor","year":"2023","unstructured":"Taylor, K. R. & Monje, M. Neuron\u2013oligodendroglial interactions in health and malignant disease. Nat. Rev. Neurosci. 24, 733\u2013746 (2023).","journal-title":"Nat. Rev. Neurosci."},{"key":"1956_CR3","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.81982","volume":"12","author":"S Pajevic","year":"2023","unstructured":"Pajevic, S., Plenz, D., Basser, P. J. & Fields, R. D. Oligodendrocyte-mediated myelin plasticity and its role in neural synchronization. eLife 12, e81982 (2023).","journal-title":"eLife"},{"key":"1956_CR4","doi-asserted-by":"publisher","first-page":"eaba6905","DOI":"10.1126\/science.aba6905","volume":"374","author":"G Bonetto","year":"2021","unstructured":"Bonetto, G., Belin, D. & K\u00e1rad\u00f3ttir, R. T. Myelin: a gatekeeper of activity-dependent circuit plasticity? Science 374, eaba6905 (2021).","journal-title":"Science"},{"key":"1956_CR5","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1038\/nrn4023","volume":"16","author":"RD Fields","year":"2015","unstructured":"Fields, R. D. A new mechanism of nervous system plasticity: activity-dependent myelination. Nat. Rev. Neurosci. 16, 756\u2013767 (2015).","journal-title":"Nat. Rev. Neurosci."},{"key":"1956_CR6","doi-asserted-by":"publisher","DOI":"10.1126\/science.1252304","volume":"344","author":"EM Gibson","year":"2014","unstructured":"Gibson, E. M. et al. 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