]: Rett syndrome (RS) predominantly affects girls, and is associated in most cases with mutations in the MeCP2 gene. Pathogenetic mechanisms of RS are unknown, but the investigators'studies support the overall hypothesis that the genetic defect disrupts maturation of neurons and their interconnections during rapid brain growth when synapses are formed and pruned. Five interactive projects will test this hypothesis with the ultimate goal of providing rational treatments. Project I will determine the natural history of the disease and biological basis for phenotypic variability by neurological, neuroimaging, and molecular approaches. Treatment with a NMDA/glutamate channel blocker will be instituted to prevent excitotoxicity and provide neuroprotection. Project IB will establish the status of the cholinergic system in vivo by single photon emission computerized tomography (SPECT) measurement of vesamicol binding as a function of age, and identify RS patients for treatment with anticholinesterase inhibitors. Also, the effect of ketamine-induced blocking of glutamate receptors on dopamine release will be investigated. In addition, MR-spectroscopy (MRS) will determine changes in glutamate with age, and efficacy of therapy with glutamate antagonists. Finally, longitudinal volumetric MRI analyses will assess age-related and regional changes. Project II will utilize cultured olfactory receptor neurons (ORNs) as a model of neuronal involvement in RS, in which effects of various mutations in MeCP2 and therapeutic interventions will be studied. Project III will pursue recent observations of extranuclear MeCP2 to characterize MeCP2 expression and subcellular localization in lymphocytes and brain of RS patients with and without different MeCP2 mutations, and in related animal models. Transcriptional regulator complexes in cellular and tissue samples will be characterized. Functional consequences of MeCP2 deficit in lymphocytes and brain from RS patients and animal models will also be delineated by patterns of histone acetylation. Project IV will determine the effect of altered MeCP2 expression on glutamate receptor ontogeny, cortical plasticity, and effect of altered MeCP2 expression on cerebellar development;examine morphological, neurological, and behavioral differences in mice with various MeCP2 mutations. Cortical as well as cerebellar granule neurons from mutant mice will also be cultured and methods to restore MeCP2 function will be explored.
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