Rett syndrome (RTT) is an X-linked dominant disorder caused by loss-of-function mutations in the gene encoding methyl CpG binding protein 2 (MECP2). Studies of human patient samples and animal models suggest that MECP2/MeCP2 may play essential roles In neuronal maturation and synapse formation/maintenance during development. The neurobiology of MeCP2 in neuronal development remains to be fully characterized, in the dentate gynjs of the hippocampus, new granule neurons are continuously generated from neural progenitors throughout life in all mammals examined, including humans. Adult hippocampal neurogenesis is dynamically regulated by physiological and pathological stimuli and believed to be involved in specific brain functions, such as leaming and memory. Defect in adult neurogenesis has also been implicated in certain brain disorders. Adult neurogenesis recapitulates the complete neuronal developmental process in a mature brain environment, including proliferation and fate specification of neural progenitors, neuronal morphogenesis, migration, axon and dendritic development, and synapse development by neuronal progeny. Our recent studies and others showed that neuronal development in the adult brain follows a stereotypic pattern in reaching same milestones as in embryonic neurogenesis, yet the integration process for adult-born neuron is significantly prolonged. Such a stereotypic and prolonged development process for a single neuronal subtype (dentate granule cell) in a relative """"""""steady-state"""""""" of mature brain offers a unique model system to investigate mechanisms of neuronal development in vivo in a great detail. We have developed a """"""""single-cell genetic'approach for studying the development of newborn granule cells in vivo using a combination of immunocytochemistry, multi-photon confocal microscopy, electron microscopy and electrophysiology. In the cun-ent project, we aim to examine the role and underiying mechanisms of MeCP2 in postnatal hippocampal neurogenesis in vivo with the following hypothesis: MeCP2 regulates the formation, maturation and maintenance of GABAergic and glutamatergic synapses of new neurons in the adult brain. Our project, addressing in great detail the cell autonomous roles of MeCP2 in vivo, will contribute from a unique aspect to the main goal of the whole center in understanding the molecular basis of RTT. Findings from these studies will be cross-compared with those from the olfactory system (Project 2) to elucidate similarities and differences of neuronal functions of MeCP2 in different developmental stages and brain regions. Random X-inactivation of MECP2 occurs in female and even those with favorable skewing of X inactivation and predominant expression of the WT MECP2 allele exhibit learning disability. Our model system examining individual neurons with MeCP2 dysfuncl^tion in a normal neuronal environment thus have significant clinical implications for the pathophysiology and etiology of RTT. n addition, RTT normally manifests at 6-18 months of age well beyond the primary neurogenesis, our studies of functional roles of MeCP2 in postnatal neurogenesis may thus provide additional novel insights. More importantly, such in vivo system provides a platform for exploring pharmacological and behavioral therapeutic approaches that can be eventually applied in humans to overcome such brain disorder (Project 1), the ultimate goal of the center.
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