Research
Rett Syndrome Program
Lisa Monteggia, Ph.D.

Investigating the epigenetics of Rett syndrome

Loss of function mutations in the Methyl-CpG binding protein 2 (MECP2) gene leads to Rett syndrome, a neurodevelopmental disorder observed primarily in females. Dr. Monteggia’s research lab has shown in mouse models that selective deletion of MECP2 in neurons in the forebrain is sufficient to replicate Rett-like phenotypes. Moreover, their 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 of Rett syndrome.

Dr. Monteggia has expanded this work to MECP2 duplication syndrome, a neurodevelopmental disorder caused by MECP2 gain of function. Her lab has shown that MECP2 overexpression selectively in the central nervous system 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, the Monteggia lab also has 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.