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Fragile X mental retardation (FMR) protein is a complex regulator of RNA and synaptic plasticity implicated in fragile X\u2010associated tremor\/ataxia syndrome, which features ataxia and increased<jats:italic>Fmr1<\/jats:italic>\u00a0mRNA expression resulting from epigenetic dysregulation of FMRP. We recently demonstrated that acute ethanol\u2010induced ataxia is associated with increased cerebellar<jats:italic>Fmr1<\/jats:italic>\u00a0gene expression via histone modifications in rats, but it is unknown whether similar behavioral and molecular changes occur following chronic ethanol exposure. Here, we investigated the effects of chronic ethanol exposure on ataxia and epigenetically regulated changes in<jats:italic>Fmr1<\/jats:italic>expression in the cerebellum.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Male adult Sprague\u2010Dawley rats were trained on the accelerating rotarod and then fed with chronic ethanol or a control Lieber\u2013DeCarli diet while undergoing periodic behavioral testing for ataxia during ethanol exposure and withdrawal. Cerebellar tissues were analyzed for expression of the<jats:italic>Fmr1<\/jats:italic>\u00a0gene and its targets using a real\u2010time quantitative polymerase chain reaction assay. The epigenetic regulation of<jats:italic>Fmr1<\/jats:italic>\u00a0was also investigated using a chromatin immunoprecipitation assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Ataxic behavior measured by the accelerating rotarod behavioral test developed during chronic ethanol treatment and persisted at both the 8\u2010h and 24\u2010h withdrawal time points compared to control diet\u2010fed rats. In addition, chronic ethanol treatment resulted in up\u2010regulated expression of<jats:italic>Fmr1<\/jats:italic>\u00a0mRNA and increased activating epigenetic marks H3K27 acetylation and H3K4 trimethylation at 2 sites within the<jats:italic>Fmr1<\/jats:italic>promoter. Finally, measurement of the expression of relevant FMRP mRNA targets in the cerebellum showed that chronic ethanol up\u2010regulated cAMP response element binding (CREB)<jats:italic>Creb1<\/jats:italic>,<jats:italic>Psd95<\/jats:italic>,<jats:italic>Grm5<\/jats:italic>, and<jats:italic>Grin2b<\/jats:italic>mRNA expression without altering<jats:italic>Grin2a<\/jats:italic>,<jats:italic>Eaa1,<\/jats:italic>or histone acetyltransferases CREB binding protein (<jats:italic>Cbp<\/jats:italic>) or<jats:italic>p300<\/jats:italic>\u00a0mRNA transcripts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These results suggest that epigenetic regulation of<jats:italic>Fmr1<\/jats:italic>and subsequent FMRP regulation of target mRNA transcripts constitute neuroadaptations in the cerebellum that may underlie the persistence of ataxic behavior during chronic ethanol exposure and withdrawal.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.14691","type":"journal-article","created":{"date-parts":[[2021,8,28]],"date-time":"2021-08-28T07:26:34Z","timestamp":1630135594000},"page":"2006-2016","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Persistence of cerebellar ataxia during chronic ethanol exposure is associated with epigenetic up\u2010regulation of<i>Fmr1<\/i>gene expression in rat cerebellum"],"prefix":"10.1111","volume":"45","author":[{"given":"Russell S.","family":"Dulman","sequence":"first","affiliation":[{"name":"Center for Alcohol Research in Epigenetics Department of Psychiatry University of Illinois at Chicago Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Auta","sequence":"additional","affiliation":[{"name":"Center for Alcohol Research in Epigenetics Department of Psychiatry University of Illinois at Chicago Chicago Illinois 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