Loss of function mutations in the X-linked gene encoding the transcriptional repressor, methyl-CpG binding protein 2 (MECP2) results in the development of Rett syndrome. We propose that MeCP2 dysfunction results in abnormal excitatory-inhibitory neuronal activity. Objective of this research proposal is to elucidate the physiological and pathophysiological role of MeCP2 expression on central synapse function and synapse formation. We will study the impact of altered MeCP2 expression on synaptic function of glutamatergic and GABAergic central synapses. We will further examine whether the downstream factor(s) that are critically regulated by MeCP2 are acting at the pre- or postsynapse AND attempt to identify candidate molecules by measuring their expression levels in the MeCP2 mouse models.
We will attempt to rescue the synaptic phenotypes by normalizing expression levels of the candidate molecules. These studies should provide important insights in the pathophysiology of RTT and other autism related developmental disorders.
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