Abstracts

Summary: Tuberous sclerosis complex (TSC) is a genetic disorder that manifests with early life epilepsy, often intractable to conventional antiepileptic therapies, tumors, and frequently cognitive impairment. The elucidation of the neurobiology of this condition has revealed a role for rapamycin, an inhibitor of mTOR pathway, as a potential therapy. An increasing number of studies have recently supported the positive therapeutic effect of rapamycin in animal models of TSC and extended its potential usefulness in other seizure models. This investigators workshop will aim to summarize these advances and provide a forum to discuss and better understand the broad range of involvement of the mTOR pathway and rapamycin analogs in the neurobiology of epilepsies and their treatment. Dr Peter Crino (University of Pennsylvania Medical Center) will describe how several neurobehavioral syndromes associated with autism, cognitive disability, and epilepsy including TSC, autism with macrocephaly, focal cortical dysplasias, and the newly described Pretzel syndrome are linked to the mTOR pathway. Dr Crino will use TSC as the platform but will extend the discussion to these related disorders as an attempt to generate a broad view of the role of mTOR in brain function. Dr Michael Wong (Washington University) will present recent work from his group documenting the importance of mTOR signaling in epileptogenesis in mouse models of TSC and demonstrating antiepileptogenic actions of mTOR inhibitors in these models. Dr Paul Buckmaster (Stanford University School of Medicine) will describe recent findings from his lab indicating that focal, unilateral infusion of rapamycin into the dorsal hippocampus of rats subjected to pilocarpine-induced status epilepticus suppresses the development of mossy fiber sprouting in the dentate gyrus. Suppression required continuous rapamycin administration. Rapamycin however did not reverse the already established axon reorganization. Dr Emmanuel Raffo (Albert Einstein College of Medicine) will present evidence from the multiple hit rat model of infantile spasms (AECOM patent 2080216183) that indicates that daily rapamycin administration, after the onset of spasms, reduces the frequency of spasms, in a dose-dependent manner. To attempt to bridge the experimental data with the experience from clinical trials as well as amplify on the role of the mTOR pathway in the neurobiology of human epilepsies, the workshop will include Dr David Neal Franz (Cincinnati Children's Hospital Medical Center), Dr Elizabeth Thiele (Massachussets General Hospital, Boston) and Dr Peter Crino as discussants. Supported by: NIH/NINDS NS045877, NS040502, NS056872, NS039110, NS040276, NS062947 and grants from PACE, IRSF, Tuberous Sclerosis Alliance, CURE, NCRR, and the Heffer Family Foundation.