Rett Syndrome (RTT) is a genetic neurodevelopmental disorder in girls affecting 1 in 10,000 births that is characterized by mental retardation, seizures, repetitive behaviors and abnormalities in social interactions. Mutations in the methyl-CpG-binding protein 2 gene (MECP2) have been found to be responsible for the majority of cases of RTT. A striking feature of this disorder is the initial apparent normal development that is followed by a regression in communicative and locomotive abilities. There is growing evidence that synaptic connections are abnormal in RTT. However, the phase at which synapse development that is disrupted is still unclear. Are synapses formed incorrectly from the start? Or do synapses form normally, but then fail to strengthen appropriately? Is the refinement process by which excess connections are eliminated abnormal? Or after normal development, does the brain fail to maintain synapses properly? To address these questions, we propose to study synaptic function during development of the visual thalamus in Mecp2 mutant mice, mouse models for the study of RTT. One model system in which a series of functional developmental phases is well characterized is the retinogeniculate synapse, the connection between retinal ganglion cells in the eye and relay neurons in the visual thalamus, making this a good assay for synapse development. Using electrophysiological techniques, we have previously shown that development of this synapse involves three distinct phases. After the first phase in development, when synapses are initially formed, there are two subsequent periods of intense synaptic remodeling. The second phase of development occurs around the time of eye opening when some retinal inputs to a given relay neuron are strengthened while other inputs are eliminated. A third phase occurs later in development when changes in sensory experience can activate the remodeling of synaptic connections, a process thought to be necessary for the adaptation of synaptic circuits to sensory experience. Here, we will examine synapse development in two Mecp2 mouse models for RTT, one in which the entire Mecp2 gene is disrupted (Mecp2-/y), and the other in which the Ser421 residue of the endogenous MeCP2 protein, a site of neuronal activity-dependent modification, has been replaced with an alanine residue (Mecp2S421A/y). Phosphorylation of this serine has previously been implicated in the regulation of dendritic and spine morphology in vitro. We will test two hypotheses: 1) Disruption of the normal response to sensory experience underlies the developmental regression observed in RTT, and 2) that this phase in synapse development is regulated by phosphorylation of the Ser421 residue of the MeCP2 protein. Thus we will evaluate synaptic strength and connectivity over development and in response to changes in sensory experience. This information, in turn, will guide our future design of therapeutic interventions for children with RTT. PUBLIC HEALTH RELEVANCE: In this grant we propose to study the formation of synaptic circuits in Mecp2 mouse models for Rett Syndrome and other Autism Spectrum Disorders. By identifying the stage of synapse development that is disrupted in Mecp2 mice, we can begin to elucidate the mechanisms that are important in normal synapse development. Moreover, by characterizing the potential plasticity of these synapses in Mecp2 mice, we will test whether synaptic circuits in these mouse models can be rewired to correct for abnormal synaptic connections. The results from these studies may help guide the design future therapies for Rett Syndrome and Autism Spectrum Disorders.