The a signify 0.05 compared to vehicle or simvastatin treated wild type group while b denote 0.05 with respect to vehicle treated AS group (one way ANOVA with HolmCSidak test). Open in a separate window FIGURE 9 Simvastatin treatment increases BDNF expression in primary cortical neurons of AS mice. to primary cortical neuronal culture prepared from AS mice embryo also rescues altered acetylation of histones H3 and H4 and the level of BDNF. These results suggest that simvastatin could be a promising drug for the treatment of AS. gene (situated within 15q11-q13 locus) also reported in a subcategory of AS patients (Albrecht et al., 1997; Kishino et al., 1997; Matsuura et al., 1997; Fang et al., 1999). These findings strongly indicate that is one of the potential candidate genes for the AS. Furthermore, gene is paternally imprinted in the neuron (Albrecht et al., 1997; Yamasaki et al., JNJ-40411813 2003). Therefore, loss of function mutations in the maternal gene could lead to its complete absence of expression in neurons. gene encodes for a 100 kDa globular protein known as E6AP/UBE3A, which is initially characterized as a E3 ubiquitin ligase that selectively targets wide range of cellular proteins for their ubiquitination and subsequent proteasomal degradation (Huibregtse et al., 1995). UBE3A also acts as a co-activator of steroid hormone receptors and regulates the expression JNJ-40411813 of their target genes (Ramamoorthy and Nawaz, 2008). Increasing evidence now indicates that the ubiquitin ligase function of Ube3a is crucial in regulating synapse development and synaptic function (Greer et al., 2010; Pignatelli et al., 2014; Sun et al., 2015, 2018; Kim et al., 2016). AS mice also exhibit impaired activity-driven dendritic spine maintenance in hippocampal CA1 as well as cortical layer III and V pyramidal neurons (Kim et al., 2016). Further studies reveal that the absence of Ube3a leads to aberrant increase in the level of activity-regulated cytoskeletal associated protein (Arc), Ephexin5 (a RhoA guanine nucleotide exchange factor) and a small conductance calcium-activated potassium channel (SK2), which might be linked with altered excitatory synaptic transmission, synapse formation and experience-dependent synaptic remodeling observed in AS mice (Yashiro et al., 2009; Greer et al., 2010; Margolis et al., 2010; Sato and Stryker, 2010; Sun et al., 2015). Although, substantial progress have been made in understanding the pathogenic mechanism of AS, presently there is no actual therapy. The reactivation of dormant paternal allele of is being considered one of the promising therapeutic strategies (Malpass, 2012). In one study, topoisomerase inhibitors are revealed to unsilence the paternal expression by inhibiting the large non-coding antisense RNA transcript (UBE3A-ATS) (Huang et al., 2012). Nonetheless, therapeutic opportunities of these topoisomerase inhibitors in animal models are yet to be understood. In another study, antisense oligonucleotide of UBE3A-ATS is shown to activate the paternal and subsequently improves the behavioral deficit in AS mice (Meng et al., 2015). Few reports in mice models also indicate that Ube3a replacement at early developmental stage might be crucial in restoring majority of AS phenotypes (Silva-Santos et al., 2015; JNJ-40411813 Gu et al., 2019). Chromatin remodeling through post-translational modification in histones play a crucial role in modulating synaptic function and plasticity (Graff et al., 2011; Penney and Tsai, 2014; Whittle and Singewald, 2014). Histones acetylation is implicated in increased synapse formation, induction in hippocampal long-term potentiation and memory consolidation (Bousiges et al., 2010; Peleg et al., 2010; Mews et al., 2017). In other studies, histone deacetylase 2 (HDAC2) is reported to negatively regulate the synaptic function and plasticity and consequently influence the memory formation (Guan et al., 2009; Graff et al., 2012). Recently, we observed aberrantly increased HDAC1 and HDAC2 activities in adult AS mice brain, which might be linked with the altered synaptic function and plasticity in these mice (Jamal et al., 2017). However, the mechanistic basis and result of improved Mouse monoclonal to CD4.CD4 is a co-receptor involved in immune response (co-receptor activity in binding to MHC class II molecules) and HIV infection (CD4 is primary receptor for HIV-1 surface glycoprotein gp120). CD4 regulates T-cell activation, T/B-cell adhesion, T-cell diferentiation, T-cell selection and signal transduction HDAC1/2 activities are not known. In the present study, we 1st report the aberrantly improved HDAC1/2 activities in AS mice mind is definitely observed from early developmental days (as early as from embryonic days 16). Subsequently, we find that Ube3a is not involved in the degradation of HDAC1/2 rather it regulates their transcription. Up-regulation of HDAC1/2 activities in AS mice mind prompted us to investigate the effect of HDAC1/2 inhibitor in rescuing of behavioral deficits in these mice. We have chosen simvastatin, because this FDA authorized brain penetrating drug not only inhibits HDAC1/2 activities but also induces the manifestation of neurotropic element BDNF apart from its popularly known HMG CoA reductase enzyme inhibition (Lin et al., 2008; Roy et al., 2015). We find that oral administration of simvastatin partially restored modified HDAC1/2 activities and.
