This is an individual National Research Service Award for pre-doctoral research training, which provides support for promising doctoral candidates who will be performing dissertation research and training in a scientific health-related field. Rett syndrome (RTT) is a progressive neurodevelopmental disease caused predominantly by loss-of-function mutations in the X-linked gene encoding the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2). Recent reports reveal that producing too much MeCP2 is also detrimental to neurological function. This project 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. The study will help elucidate the impact of altered MeCP2 levels on neuronal function and identify the contribution of global excitatory and inhibitory neuronal activity to Rett syndrome phenotypes. This research will give insight into RTT pathogenesis and provide new target pathways for investigating potential therapeutic interventions.