MeCP2 phosphorylation is required for modulating synaptic scaling through mGluR5.

MeCP2 (methyl CpG binding protein 2) is a key player in recognizing methylated DNA and interpreting the epigenetic information encoded in different DNA methylation patterns. The functional significance of MeCP2 to the mammalian nervous system is highlighted by the discovery that mutations in the MECP2 gene cause Rett syndrome (RTT), a devastating neurological disease that shares many features with autism. Synaptic scaling is a form of non-Hebbian homeostatic plasticity that allows neurons to regulate overall excitability in response to changes in network neuronal activity levels. While it is known that neuronal activity can induce phosphorylation of MeCP2 and that MeCP2 can regulate synaptic scaling, the molecular link between MeCP2 phosphorylation and synaptic scaling remains undefined. We show here that MeCP2 phosphorylation is specifically required for bicuculline-induced synaptic scaling down in mouse hippocampal neurons and this phenotype is mediated by mGluR5 (metabotropic glutamate receptor 5). Our results reveal an important function of MeCP2 in regulating neuronal homeostasis and may eventually help us understand how MECP2 mutations cause RTT.