MeCP2 is a transcriptional repressor critical for normal neurological function. Rett syndrome (RTT) is a progressive neurodevelopmental disease caused by predominantly loss of function mutations in the X-linked gene encoding the transcriptional repressor, methyl-CpG-binding protein 2 (MECP2) genes. Classic RTT patients exhibit a spectrum of neurological phenotypes that include tremors, ataxia, seizures, stereotypes, anxiety, mental retardation, breathing dysrhythmias, and loss of motor skills and language. Recent reports reveal that overexpression of MeCP2 is also detrimental to neurological function and is a frequent cause of mental retardation and progressive neurological symptoms in males. I hypothesize that misregulation of MeCP2 levels results in abnormal excitatory and inhibitory neuronal activity, which leads to the spectrum of neurological phenotypes. In order to test this hypothesis, I will examine the neurophysiological properties of neurons upon loss or doubling of MeCP2 develop and characterize conditional Mecp2 knockout mouse models specific to excitatory and inhibitory neurons, and assess their behavioral and neurophysiological phenotypes. PUBLIC HEALTH RELEVANCE: The research proposal seeks to understand the impact of altered MeCP2 levels on neuronal function and to identify the contribution of global excitatory and inhibitory neuronal activity to RTT phenotypes. Ultimately, the proposal will provide important insight into MeCP2 regulation of neuronal function and the neurobiological alterations resulting in RTT pathogenesis and provide new target pathways for investigating potential therapeutic interventions.