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Cell Type-Specific Contributions to the TSC Neuropathology

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Technical Report,01 Aug 2017,31 Jul 2018

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Rutgers University New Brunswick United States

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Mutations in the human TSC2 gene cause tuberous sclerosis complex TSC, a developmental disorder characterized by tumor susceptibility and neurological manifestations. To better understand the disease we generated an animal model in which the mouse Tsc2 gene is disrupted exclusively in excitatory neurons of the forebrain. We are investigating how heterozygous and homozygous Tsc2 mutations affect the development of mutant excitatory neurons as well as other surrounding brain cells, in vivo and in vitro. During this second year of support we focused on Major Task 1 In vivo characterization of heterozygous and homozygous NEX-Tsc2 mice. Specifically, we performed experiments described under Subtask 1 Animal breeding for in vivo studies, Subtask 3 Analysis of neuronal development and synaptogenesis, Subtask 4 Analysis of non-cell autonomous differentiation and signaling defects, and Subtask 6 Epilepsy and seizure susceptibility. We found that heterozygous mutations of Tsc2 in the excitatory neurons of the forebrain have no detectable effects on neuronal differentiation but increase seizure susceptibility, whereas homozygous loss disrupts the maturation not only of excitatory neurons cell-autonomous but also disrupts the development of inhibitory synapses non cell-autonomous effect and cause recurrent seizures.

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  • Medicine and Medical Research

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