Neurology & Neurophysiology

Biography

Intractable seizures plague approximately a third of epilepsy patients. Despite their prevalence, the mechanisms underlying intractable seizures remain unclear and difficult to study. One factor clouding our understanding of seizure intractability stems from existing animal models of epilepsy, which have not specifically modeled intractable seizures or genetic disorders that often associate with intractable seizures, like Focal Cortical Dysplasia (FCD) or Tuberous Sclerosis Complex (TSC). New animal models are greatly needed to understand the underlying causes of intractable seizures and develop new therapies aimed at these indications. Using in utero electroporation to transfect a small population of neurons in vivo with constitutively active mutant of Ras homolog enriched in brain (RhebCA), we have successfully developed a new mouse model of spontaneous epilepsy based on the genetic etiology of mTOR-o-pathies. This model recapitulates both anatomical and behavioral phenotypes of human TSC and FCD. RhebCA transfected animals develop focal cortical malformations that contain dysplastic neurons, cortical dyslamination and white matter heterotopia. Seizures also spontaneously develop as early as postnatal day18, and persist throughout entire lifespan of the animals (2 years). Seizures are the only complication these animals have, otherwise they are completely healthy, making them ideal subjects to study mechanistic causes of seizures and seizure-dependent downstream behavioral and physiological effects. With this model, we have elucidated several mechanisms that contribute to seizure-genesis in TSC and FCD. Lastly, we also use this model to develop new therapies, including novel cannabinoids and RNA interference approaches to mitigate refractory seizures

Research Interest

Neuroscience , Neurosurgery