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CMT1A is caused by a duplication of the\n                    <jats:italic>PMP22<\/jats:italic>\n                    gene, which leads to Schwann cell differentiation defects and dysmyelination of the peripheral nerves. The epigenetic regulator histone deacetylase 3 (HDAC3) has been shown to negatively regulate myelination as well as its associated signaling pathways, PI3K-AKT and MAPK-ERK. We showed that these signaling pathways are indeed downregulated in the C3-PMP22 mouse model, similar to what has been shown in the CMT1A rat model. We confirmed that early postnatal defects are present in the peripheral nerves of the C3-PMP22 mouse model, which led to a progressive reduction in axon caliber size and myelination. The aim of this study was to investigate whether pharmacological HDAC3 inhibition could be a valuable therapeutic approach for this CMT1A mouse model. We demonstrated that early treatment of CMT1A mice with the selective HDAC3 inhibitor RGFP966 increased myelination and myelin g-ratios, which was associated with improved electrophysiological recordings. However, a high dose of RGFP966 caused a decline in rotarod performance and a decline in overall grip strength. Additionally, macrophage presence in peripheral nerves was increased in RGFP966 treated CMT1A mice. We conclude that HDAC3 does not only play a role in regulating myelination but is also important in the neuroimmune modulation. Overall, our results indicate that correct dosing of HDAC3 inhibitors is of crucial importance if translated to a clinical setting for demyelinating forms of CMT or other neurological disorders.\n                  <\/jats:p>","DOI":"10.1007\/s12035-022-02782-x","type":"journal-article","created":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T02:02:47Z","timestamp":1648000967000},"page":"3414-3430","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["HDAC3 Inhibition Stimulates Myelination in a CMT1A Mouse Model"],"prefix":"10.1007","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4184-0693","authenticated-orcid":false,"given":"Robert","family":"Prior","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stijn","family":"Verschoren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2893-752X","authenticated-orcid":false,"given":"Katlijn","family":"Vints","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7485-4397","authenticated-orcid":false,"given":"Tom","family":"Jaspers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6924-4631","authenticated-orcid":false,"given":"Elisabeth","family":"Rossaert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2779-3357","authenticated-orcid":false,"given":"Yvonne E.","family":"Klingl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6659-9595","authenticated-orcid":false,"given":"Alessio","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Hersmus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4010-2357","authenticated-orcid":false,"given":"Philip","family":"Van Damme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0104-4067","authenticated-orcid":false,"given":"Ludo","family":"Van Den Bosch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,3,23]]},"reference":[{"key":"2782_CR1","doi-asserted-by":"crossref","unstructured":"Matsunami N, Smith B, Ballard L, Lensch MW, Robertson M, Albertsen H, Hanemann CO, Miiller HW, Bird TD et al (1992) Peripheral myelin protein-22 gene maps in the duplication in chromosome 17p11.2 associated with Charcot-Marie-Tooth 1A. 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