Similarly, many Selleck JAK inhibitor types of long-lasting synaptic plasticity such as LTP, required for memory consolidation, initiate complex gene transcription programs (Alberini, 2008, Davis and Squire, 1984 and Frey et al., 1988). In fact, activity-dependent changes in gene expression have long been implicated in learning and memory processes in the CNS (Flavell and Greenberg, 2008 and Loebrich

and Nedivi, 2009). Therefore, epigenetic modifications may play a similar role in the CNS, initiating functional consequences within a cell or a circuit by modulating gene expression. Accumulating evidence already supports the hypothesis that gene expression programs are a functional readout of epigenetic marking

in the CNS in memory formation. As reviewed above, SB431542 solubility dmso these gene programs are largely dependent on intracellular signaling cascades (such as the MAPK pathway) and activation of critical transcription factors that bind to specific sequences in gene promoter regions. Indeed, it may be this specificity in transcription factor binding sites that leads certain signal transduction cascades to target specific genes and induce specific epigenetic changes. For example, when phosphorylated, CREB binds to cAMP responsive element sites in gene promoters and interacts with CBP, which possesses HAT activity (Gonzalez et al., 1989, Montminy et al., 1990a, Montminy et al., 1990b and Silva found et al., 1998). Interestingly, stimuli that produce long-lasting LTP also increase CREB phosphorylation in the hippocampus (Deisseroth et al., 1996), and CREB manipulations impair memory formation in multiple tasks (Silva et al.,

1998). Likewise, blocking cAMP-dependent transcription alone is sufficient to impair LTP maintenance (Frey et al., 1993 and Impey et al., 1996). Thus, given that transcriptional machinery such as CREB has long been established as a regulator of cellular and behavioral memory (Frank and Greenberg, 1994, Shaywitz and Greenberg, 1999 and Silva et al., 1998), it is perhaps not surprising that epigenetic modifications have been found to interact with these systems (Chahrour et al., 2008 and Renthal and Nestler, 2008). Other epigenetic targets have also been identified in regulating overall transcription rates of specific genes in the establishment, consolidation, and maintenance of behavioral memories (Guan et al., 2009, Lubin et al., 2008, Miller et al., 2008, Miller et al., 2010 and Peleg et al., 2010). Specifically, contextual fear conditioning induces a rapid but reversible methylation of the memory suppressor gene PP1 within the hippocampus and demethylation of reelin, a gene involved in cellular plasticity and memory ( Miller and Sweatt, 2007).