, 2009, Levenson et al., 2004, Lubin and Sweatt,

2007, Peleg et al., 2010 and Swank and Sweatt, 2001). For example, contextual fear conditioning, a hippocampus-dependent form of memory, coincides with increases in H3K9 dimethylation, H3K4 trimethylation, H3S10 phosphorylation, and H3S10/H3K14 phosphoacetylation in the CA1 region of the hippocampus (Chwang et al., 2006 and Gupta et al., 2010). Moreover, contextual fear conditioning coincides with enhanced acetylation at multiple sites on the tails of H3 and H4, including H3K9, H3K14, H4K5, H4K8, and H4K12 in the hippocampus (Peleg et al., 2010). None of these changes occur in control animals that are exposed to the same context but receive no fear conditioning, indicating that these modifications are specific

to associative learning. Importantly, interference with the molecular machinery this website that regulates histone acetylation, phosphorylation, and Y-27632 research buy methylation disrupts associative learning and long-term potentiation (LTP; a cellular correlate of memory) (Alarcón et al., 2004, Chwang et al., 2007, Fischer et al., 2007, Gupta et al., 2010, Korzus et al., 2004, Koshibu et al., 2009, Levenson et al., 2004 and Vecsey et al., 2007). Specifically, upregulating histone acetylation using HDAC inhibitors enhances memory formation and LTP (Levenson et al., 2004), whereas genetic mutations in CREB binding protein (CBP), a known HAT, disrupts memory formation and LTP (Alarcón et al., almost 2004). Likewise, mice with deletion of a specific HDAC (HDAC2) display enhanced fear conditioning and hippocampal LTP, whereas overexpression of HDAC2 in the hippocampus impairs memory and blunts LTP (Guan et al., 2009). Similarly for histone phosphorylation, inhibition of nuclear PP1, which is implicated in the removal of histone phosphorylation marks, results in improved long-term memory (Koshibu et al., 2009), whereas genetic deletion of specific histone methyltransferases impairs memory formation (Gupta et al., 2010). Overall, these modifications are consistent with the

involvement of a “histone code” in learning and memory, in which specific sets of changes are produced in response to specific types of behavioral experiences, and these modifications are necessary for memory formation and/or consolidation. However, in the context of learning and memory, it appears that it is the combination of histone modifications, rather than the sum of individual modifications, that produces unique changes in gene expression required for memory formation. Specifically, the co-occurrence of acetylation at H3K9, H3K14, H4K5, H4K8, and H4K12 in the hippocampus following fear conditioning is associated with changes in the transcription of hundreds of genes in young mice (Peleg et al., 2010). In contrast, elderly mice that lack acetylation only at H4K12 following fear conditioning manifest learning deficits and show almost no conditioning-induced changes in gene expression.