Role of MeCP2 in Circuitry Development and Plasticity

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DESCRIPTION (provided by applicant): Rett syndrome is a neurodevelopmental disorder caused by mutations in the methyl CpG binding protein 2 gene (Mecp2). Loss of Mecp2 function results in defects in neuronal maturation, synaptogenesis and dendritic development in the central nervous system. MeCP2 is a transcription regulator that binds preferentially to methylated CpG dinucleotides sequences. Identification of MeCP2 target genes and understanding their functions in the establishment of functional circuitry is critical for future development of therapeutic approaches. Several unique characteristics make the vertebrate olfactory system an excellent model to study MeCP2 function. 1). Olfactory sensory neurons are the sole neuronal type in the olfactory epithelium. This will facilitate the identification of transcription regulations without the interference of mixed regulatory effects that are seen in mixed neuronal populations of cortical tissue. 2) The intricate and precise olfactory connections allow identification of axon mistargeting out of their specific olfactory bulb foci. 3) Manipulation of neuronal activity at the physiological level can be easily achieved due to the accessibility of olfactory sensory neurons in the nasal cavity. The goal of this study is to use the olfactory system as a model to further define MeCP2 function in circuitry formation and refinement. In Aim 1, we will test the hypothesis that MeCP2 is required for the formation of precise adult olfactory connections. In Aim 2, we will test the hypothesis that MeCP2 regulates expression of cell adhesion molecules in olfactory sensory neurons. In Aim 3, we will test the hypothesis that MeCP2 tunes transcription of activity-regulated cell adhesion molecules in the olfactory system. Through this study, we hope to gain better understanding of MeCP2 function not only in the olfactory system but also in other regions of the central nervous system.