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Disruption of BDNF gene expression is a key to the development of symptoms in Huntington's disease (HD), a fatal neurodegenerative condition. Abnormal epigenetic modifications are associated with reduced gene expression in late\u2010stage HD but such regulation of BDNF gene expression has yet to be investigated. We hypothesized that BDNF gene expression is altered in the HD hippocampus of pre\u2010motor symptomatic R6\/1 transgenic HD mice, correlating with a change in the DNA methylation profile. The effects of wheel\u2010running and environmental enrichment on wild\u2010type mice, in association with a proposed environment\u2010mediated correction of BDNF gene expression deficits in HD mice, were also investigated. Using real\u2010time PCR, levels of total BDNF mRNA were found to be reduced in the hippocampus of both male and female HD mice. Wheel\u2010running significantly increased total BDNF gene expression in all groups of mice except male HD mice. In contrast, environmental enrichment significantly increased expression only in male wild\u2010type animals. Further quantification of BDNF exon\u2010specific transcripts revealed sex\u2010specific changes in relation to the effect of the HD mutation and differential effects on gene expression by wheel\u2010running and environmental enrichment. The HD\u2010associated reduction of BDNF gene expression was not due to increased methylation of the gene sequence. Furthermore, environment\u2010induced changes in BDNF gene expression in the wild\u2010type hippocampus were independent of the extent of DNA methylation. Overall, the results of this study provide new insight into the role of BDNF in HD pathogenesis in addition to the mechanisms regulating normal BDNF gene expression. \u00a9 2009 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/hipo.20658","type":"journal-article","created":{"date-parts":[[2009,6,4]],"date-time":"2009-06-04T19:30:39Z","timestamp":1244143839000},"page":"621-636","source":"Crossref","is-referenced-by-count":147,"title":["Wheel running and environmental enrichment differentially modify exon\u2010specific BDNF expression in the hippocampus of wild\u2010type and pre\u2010motor symptomatic male and female Huntington's disease 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