, 2011b, Lubin et al., 2008, Ma et al., 2009 and Miller and Sweatt, 2007). The near-simultaneous discoveries of a hydroxylated Fulvestrant datasheet form of

5mC (5hmC) (Kriaucionis and Heintz, 2009) and the Ten-eleven translocation (Tet) family of enzymes required for its conversion (Tahiliani et al., 2009) has now offered insight into how these changes in DNA methylation might occur. Specifically, all three Tets (TET1–TET3) have been shown to catalyze the conversion of 5mC to 5hmC as well as its further oxidation into 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), respectively (He et al., 2011, Ito et al., 2010 and Ito et al., 2011). These modified bases may then function as DNA demethylation intermediates subject to deamination, glycosylase-dependent excision, and repair resulting in a reversion back to unmodified cytosine (Bhutani et al., 2011 and Branco et al., 2012). However, it has now become apparent that 5hmC is not merely a DNA demethylation intermediate but BMN 673 research buy also functions as a stable epigenetic mark enriched within gene bodies, promoters, and transcription factor binding sites, where it may influence gene expression

(Hahn et al., 2013, Mellén et al., 2012 and Szulwach et al., 2011). In the adult brain, alterations in global DNA methylation patterns in response to neuronal activity (Guo et al., 2011a and Miller-Delaney et al., 2012) are at least partially mediated by TET1, which is both necessary and sufficient for demethylation of the fibroblast growth factor 1 (Fgf1) and the brain-derived neurotrophic factor (Bdnf) promoters in response to electroconvulsive shock ( Guo et al., 2011b). Complementary studies have shown that Bdnf is

critical for memory formation ( Bekinschtein et al., 2008 and Mizuno et al., 2000), and its promoter region undergoes rapid demethylation after associative learning in a fear conditioning paradigm in rodents ( Lubin et al., 2008), suggesting the possibility that Tet1 may contribute to memory formation. However, too at present, the role of Tet-mediated regulation of 5hmC and subsequent active DNA demethylation in relation to the expression of neuronal plasticity genes and memory has not been extensively explored, although Zhang et al. recently reported that Tet1 deletion in a knockout mouse model resulted in altered neurogenesis and a deficit in spatial memory in the Morris water maze ( Zhang et al., 2013). In this study, we sought to investigate the role of TET1 enzymatic activity in memory formation, through its ability to promote demethylation and, therefore, gene expression. We found that endogenous TET1 is expressed in neurons throughout the hippocampus and that its transcript levels are regulated by neuronal activity.