Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the presence of benign tumors, called hamartomas, which can affect virtually every organ system of the body. The hallmark of TSC and the predominant cause of morbidity in this disease are the neurological symptoms, such as epilepsy, autism and mental retardation, which occur in 95% of affected individuals. Over the last decade, significant progress has been made in identifying a function for TSC in regulating protein synthesis and cell size. However, the cause of the neurological symptoms in TSC patients has not yet been resolved. We propose a set of experiments to investigate neuronal connectivity and network formation in mouse models of TSC. These experiments are based on our recent observation that TSC pathway components are expressed in axons of hippocampal neurons at high levels starting with the initial stages of axonal polarization. Furthermore, we find that in mice lacking Tsc2, topographic mapping of connections in the brain are aberrant compared to wild-type mice. These findings have led us to hypothesize that TSC proteins are crucial not only for determining cell size, but also for determining axonal connectivity in the brain. We propose two sets of experiments to elucidate the role played by TSC1/TSC2 proteins in the establishment of axonal polarity and the mediation of axonal pathfinding. By using dissociated cultures, acute brain slices, and brain sections, we will first characterize the role of TSC proteins in the establishment of neuronal polarity. In the second phase of the project, we will characterize the role of TSC proteins in axon pathfinding and growth cone dynamics. Ultimately, our work will determine the role of TSC proteins in neuronal network formation by examining the visual pathways in Tsc-deficient mice - the best-studied and most accessible axon pathway in the central nervous system. The operations of TSC protein complex may be the key to a fuller understanding of the abnormal neural networks of TSC. Our results, thus, may suggest further avenues of exploration to illuminate the complex causes of the devastating neurological symptoms that characterize TSC.
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