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Temporal Loss of Tsc1: Neural Development and Brain Disease in Tuberous Sclerosis

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Final rept. 1 Jun 2012-31 May 2014

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The purpose of our research proposal is to determine how the deletion of Tsc1 and mTOR dysregulation affects thalamus development and function. An addition goal of our research was to use our conditional gene deletion system to test the ability of the mTOR inhibitor rapamycin to ameliorate neurological phenotypes depending upon the time and duration of treatment. During this research period, we further advanced our novel genetic approach to control Tsc1 gene deletion concomitant with cell lineage tracing and biochemical analysis to better understand the developmental aspects of Tuberous Sclerosis. A major set of findings is that we identified cellular, molecular, circuitry, and behavioral changes that occur during development and are specific to distinct temporal roles of Tsc1 and the mTOR pathway. Specifically, we showed that early embryonic deletion of Tsc1 resulted in mTOR dysregulation within 48 hours and this dysregulation persisted throughout the life of the mice this is the first report of the kinetics of mTOR dysregulation. In addition, we showed that neural circuits that connect the thalamus and cerebral cortex are disrupted by early or late deletion of Tsc1 and that the neural circuit abnormality is first observed at the end of embryogenesis five days after mTOR dysregulation. Thus, specific phenotypes emerge rapidly and others appear over a more prolonged developmental window. We then used biochemistry to show that proteins involved in synaptic architecture are altered by the early deletion of Tsc1. Finally, we show that behavioral alterations are strongly associated with the time of Tsc1 function. We initiated studies to address our additional and have begun delineate the most effective method and dose of rapamycin that can support development while at the same time effectively suppressing the mTOR pathway.

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  • Biochemistry
  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

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