Neurofibromatosis type 1 (NF1) is a common dominant genetic disorder characterized by multiple benign and malignant tumors of neural origin and, often, cognitive deficits in children. The protein encoded by NF1, neurofibromin, contains a GAP domain, known to inhibit Ras-mediated signal transduction, a pathway known to be required for both memory consolidation and long-term neuronal plasticity. The long-term goal of our research is to delineate the cellular mechanisms and signal transduction pathways underlying dendritic spine formation and plasticity. This proposal will test the hypothesis that NF1 plays an essential role in dendritic spine formation and plasticity by serving as a negative regulator for Ras (and MARK) signaling.
Our specific aims are to: 1) determine if NF1 deficiency leads to deficits in the formation and maturation of dendritic spines; 2) determine if NF1 deficiency leads to deficits in synapse formation and synaptic function; 3) determine if NF1 deficiency leads to hyperactive Ras-MAPK signaling; and 4) determine if NF1-deficient cells have an altered capacity to undergo morphological plasticity after spaced depolarizing stimuli, and whether the deficits in morphology can be rescued by manipulating Ras-MAPK signaling. Multidisciplinary approaches, including time-lapse imaging confocal microscopy, molecular imaging with FRET, quantitative immunocytochemistry, whole-cell patch-clamp recording, genetic mouse models, and pharmacological and molecular manipulations such as dominant negative constructs and small interfering RNAs (siRNAs), will be used to define the NF1 function in synapse formation and morphogenesis of dendritic spines. The combination of structural and functional analyses with the assessment of the underlying signal transduction mechanisms at the single cell level should provide better new insights into NF1 function in neurons and will shed light on the mechanism by which dysregulation of this function leads to cognitive deficits in NF1 patients. ? ?
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