Rett syndrome and epigenetics

Loss of function mutations in the Methyl-CpG binding protein 2 (MeCP2) gene leads to Rett syndrome, a neurodevelopmental disorder observed primarily in females. Our group has shown in mouse models that selective deletion of MeCP2 in neurons in the forebrain is sufficient to replicate Rett-like phenotypes. Moreover, our studies have uncovered a critical role for MeCP2 function in the regulation of synaptic transmission giving rise to an imbalance in excitation – inhibition that may underlie the behavioral deficits.

We have expanded this work to MeCP2 Duplication Syndrome, a neurodevelopmental disorder caused by MeCP2 gain of function. We have shown that MeCP2 overexpression selectively in the CNS can recapitulate many of the behavioral aspects of MeCP2 duplication syndrome and has selective bidirectional effects on synaptic transmission from that observed with MeCP2 loss of function.

In recent studies we have also been examining epigenetic factors, including histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), and the MEF2 family of transcription factors, that regulate synapse maturation and synaptic efficacy in the central nervous system. Epigenetic regulation of synapse function carries wide ranging implications that go beyond the etiology of Rett syndrome to mechanisms underlying other autism spectrum disorders as well as other psychiatric disorders.