In conjunction with histone modifications, DNA methylation plays critical roles in gene silencing through chromatin remodeling. Changes in DNA methylation perturb neuronal function, and mutations in a methyl-CpG-binding protein, MeCP2, are associated with Rett syndrome. We report that increased synthesis of brain-derived neurotrophic factor (BDNF) in neurons after depolarization correlates with a decrease in CpG methylation within the regulatory region of the Bdnf gene. Moreover, increased Bdnf transcription involves dissociation of the MeCP2-histone deacetylase-mSin3A repression complex from its promoter. Our findings suggest that DNA methylation-related chromatin remodeling is important for activity-dependent gene regulation that may be critical for neural plasticity.