Moreover, consistent with the finding that blocking DNA methylation in the anterior cingulate cortex prevents remote memory maintenance, another study reported long-lasting changes in methylation of the memory suppressor gene calcineurin within this brain area following contextual fear conditioning ( Miller et al., 2010). These changes in calcineurin methylation persisted at least 30 days following conditioning, suggesting the change is stable enough to maintain a memory over time despite ongoing cellular activity and molecular turnover. Thus, calcineurin

is an excellent candidate for a molecular storage device. Likewise, although they are too numerous to name here, histone modifications have been repeatedly associated with changes in gene transcription and expression in multiple organisms, systems, and brain subregions ( Brami-Cherrier et al., 2005, Dulac, 2010, Guan et al., Trichostatin A molecular weight 2002, Gupta et al., 2010, Koshibu et al., 2009 and Renthal and Nestler, 2008). Thus, these results reveal that even within nondividing neurons in the adult CNS, epigenetic mechanisms regulate patterns of gene expression in a functionally relevant manner. Indeed, when viewed through this lens, epigenetic changes can MDV3100 datasheet simply be viewed as one of the final steps (or perhaps the final step) in a long cascade of events that leads to learning-related

gene transcription ( Kornhauser et al., 2002, Shaywitz GPX6 and Greenberg, 1999 and Sweatt, 2001). A related means for epigenetic control of gene expression involves the unique regulation of specific protein isoforms, or differently spliced versions of the same protein. This can occur in multiple ways, such as increased expression of one exon over another competing exon or silencing of an entire exon. By regulating the expression of splice variants with different cellular functions or different affinities for effector proteins, the potential uses of the same gene locus can be expanded in a multiplicative fashion (Nilsen and Graveley, 2010). The mechanisms that regulate alternative splicing are currently unclear. However, histone modifications appear to modulate this

process by recruiting different splicing regulators that determine splicing outcome (Luco et al., 2010). DNA methylation is also likely involved in the differential expression of BDNF exons following fear learning ( Lubin et al., 2008). Contextual fear conditioning produces a rapid increase in mRNA for BDNF exon IV, thereby decreasing methylation at this locus in area CA1 of the hippocampus. Interestingly, context exposure alone (no conditioning) produced increases in BDNF exon I and VI mRNA, which also corresponded to decreased CpG methylation at these sites. Moreover, intrahippocampal infusions of the DNMT inhibitors zebularine or RG108 impaired fear memory expression, despite the fact that they increase expression of all BDNF exons in naive animals.