Rett syndrome (RTT) is an X-linked dominant disorder caused by loss-of-function mutations in the geneencoding methyl CpG binding protein 2 (MECP2). Studies of human patient samples and animal modelssuggest that MECP2/MeCP2 may play essential roles In neuronal maturation and synapseformation/maintenance during development. The neurobiology of MeCP2 in neuronal development remainsto be fully characterized, in the dentate gynjs of the hippocampus, new granule neurons are continuouslygenerated from neural progenitors throughout life in all mammals examined, including humans. Adulthippocampal neurogenesis is dynamically regulated by physiological and pathological stimuli and believed tobe involved in specific brain functions, such as leaming and memory. Defect in adult neurogenesis has alsobeen implicated in certain brain disorders. Adult neurogenesis recapitulates the complete neuronaldevelopmental process in a mature brain environment, including proliferation and fate specification of neuralprogenitors, neuronal morphogenesis, migration, axon and dendritic development, and synapsedevelopment by neuronal progeny. Our recent studies and others showed that neuronal development in theadult brain follows a stereotypic pattern in reaching same milestones as in embryonic neurogenesis, yet theintegration process for adult-born neuron is significantly prolonged. Such a stereotypic and prolongeddevelopment process for a single neuronal subtype (dentate granule cell) in a relative 'steady-state' ofmature brain offers a unique model system to investigate mechanisms of neuronal development in vivo in agreat detail. We have developed a 'single-cell genetic' approach for studying the development of newborngranule 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 underiyingmechanisms of MeCP2 in postnatal hippocampal neurogenesis in vivo with the following hypothesis: MeCP2regulates the formation, maturation and maintenance of GABAergic and glutamatergic synapses ofnew neurons in the adult brain. Our project, addressing in great detail the cell autonomous roles of MeCP2in vivo, will contribute from a unique aspect to the main goal of the whole center in understanding themolecular basis of RTT. Findings from these studies will be cross-compared with those from the olfactorysystem (Project 2) to elucidate similarities and differences of neuronal functions of MeCP2 in differentdevelopmental stages and brain regions. Random X-inactivation of MECP2 occurs in female and even thosewith favorable skewing of X inactivation and predominant expression of the WT MECP2 allele exhibitlearning disability. Our model system examining individual neurons with MeCP2 dysfuncl^tion in a normalneuronal 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, ourstudies 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 behavioraltherapeutic approaches that can be eventually applied in humans to overcome such brain disorder (Project1), the ultimate goal of the center.
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