Rett syndrome (RTT), an autism spectrum disorder, is caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2), a transcriptional regulator that binds to methylated CpG sites in promoter regions of DNA. An imbalance of excitatory and inhibitory synaptic function in the hippocampus has been implicated in neurodevelopmental disorders associated with cognitive impairments and mental retardation. Mouse cortical neurons lacking Mecp2 show low levels of neuronal activity caused by an excitation/inhibition imbalance that favors synaptic inhibition, and Mecp2 expression levels modulate excitatory synapse formation between hippocampal neurons. One of the target genes of Mecp2 transcriptional control is Brain-derived neurotrophic factor (Bdnf), a potent modulator of activity-dependent synaptic development, function and plasticity. This research will use mouse models to test whether impaired development of hippocampal inhibitory synapses due to reduced BDNF release contributes to the excitatory/inhibitory imbalance of synaptic function implicated in cognitive impairments and autism in RTT. These experiments will uncover fundamental brain mechanisms involved in the neuropathology of RTT and autism spectrum disorders and test an experimental rationale to relieve cognitive impairments and mental retardation in children with associated neurodevelopmental disorders.