To investigate the contribution of MeCP2 S421 phosphorylation in cortical circuit formation, the authors examined dendritic morphology of cortical neurons both in vitro and

in vivo from MeCP2 S421A mutant animals. Mutant cortical neurons exhibited significantly more dendritic branches and notably, this increase in dendritic complexity was found only in the apical dendritic tufts of pyramidal neurons. This finding however, differs from the reduced spine number and dendritic complexity reported in studies of MeCP2 KO null and RTT patients (Na and Monteggia, 2011). Previous work in MeCP2 null mice showed reduced cortical activity due to a shift in the balance between excitation and inhibition in layer 5 pyramidal neurons. Specifically, reduced circuit excitability GSK126 concentration was accompanied by both reduced spontaneous excitatory synaptic input and increased inhibition,

however the molecular mechanisms which underlie this shift remain largely unknown (Dani et al., 2005). What then, are the neurophysiological consequences of activity-dependent MeCP2 S421 phosphorylation and does this modification influence normal synaptic function and behavior? To address this issue, Cohen et al. (2011) analyzed spontaneous miniature inhibitory postsynaptic currents (mIPSCs) and spontaneous miniature excitatory postsynaptic currents (mEPSCs) in whole-cell recordings from layer II/III pyramidal neurons from MeCP2 S421A mutant animals and control littermates. They observed a modest increase in the amplitude of mIPSCs but no difference in either the amplitude or frequency click here of mEPSCs. Noting that a hallmark of the early stages of RTT is decreased social function, the authors next examined the behavioral responses of animals in which activity-dependent MeCP2 S421 phosphorylation was abolished. Unlike animals with complete loss of oxyclozanide function of MeCP2, MeCP2 S421A animals do not exhibit abnormalities in social interaction, motor coordination, spatial learning, or memory paradigms, but they are unable to distinguish

between novel and familiar stimuli. These findings demonstrate a role for activity-dependent phosphorylation of MeCP2 S421 in highly specific and subtle aspects of cortical neuronal morphology, synaptic function, and behaviors. Adrian Bird and colleagues have challenged the view that MeCP2 functions as a gene-specific transcriptional repressor (Skene et al., 2010). Using a newly developed biochemical fractionation technique, they reported that MeCP2 protein is almost as abundant as the number of histone octamers. They employed bisulfite sequencing and MeCP2 chromatin-immunoprecipitation assays followed by high throughput sequencing (ChIP-Seq) of mouse brain nuclei extract and discovered that MeCP2 is globally distributed across the entire mouse genome and this distribution tracks the density of methyl-CpGs.