Investigation of Cell Types Responsible for Seizure Generation in a Model of Neurofibromatosis Type 1

Up to 20% of people with neurofibromatosis type 1 (NF1) have epilepsy, but the mechanism is unknown. The purpose of this research is to determine how a mutation in the Nf1 gene leads to increased seizure susceptibility. We hypothesize increased seizure susceptibility in theNf1+/- mouse neocortex is due to increased interneuron activity. Aim 1: Determine whether loss of neurofibromin in interneurons or excitatory neurons is sufficient to increase seizure susceptibility. We are using electrophysiological and optogenetic techniques to determine effects of Nf1 mutation in interneurons or excitatory neurons at the synaptic and circuit levels. Work is in progress investigating rates of spontaneous seizures and susceptibility to kainic acid induced seizures in mice with selective loss of neurofibromin in different cell types. We are also beginning work to determine whether activation of interneurons or excitatory neurons in NF1 cortical slices will lead to increased interictal- or ictal-like events, Aim 2: Pharmacologic rescue of increased seizure phenotype. Future work will test whether MEK or mTOR inhibitors can reverse increased seizure susceptibility in NF1 in vivo and in vitro.