Tuberous sclerosis complex (TSC) is a genetic disease afflicting nearly 50,000 Americans and at least one million individuals worldwide. TSC is a devastating multi-organ disease that results in benign tumors and severe neurological manifestations. Epilepsy is a common feature of TSC, with at least 90% of affected individuals generating seizures ranging from infantile spasms to complex partial seizures. While there currently is no cure for this disease, improved therapies may be developed from a more thorough understanding of the molecular basis of epilepsy in TSC. To gain insight into this health problem, a zebrafish model of this disease has been developed by knocking-down TSC gene function using morpholino oligonucleotides. In this proposal, electrophysiological recordings and behavioral monitoring will be used to examine the hyperexcitable in TSC-deficient morphants. A comprehensive analysis of brain morphology will be performed to uncover the developmental effects of TSC deficiency. Finally, pharmacological agents, known to affect the TSC signaling pathway, will be tested for therapeutic efficacy. This proposal may provide clues into the causes of epilepsy in TSC and identify biochemical targets for treating this disease. ? ? ?
