Increased seizure susceptibility in a mouse model of neurofibromatosis type 1

Abstract

Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder linked to higher rates of epilepsy as compared with the general population. Although some epilepsy cases in NF1 are related to intracranial lesions, epileptogenic lesions are not always identified. It is unknown whether the genetic mutation itself, which leads to lower levels of the tumor suppressor protein neurofibromin, alters seizure susceptibility. The purpose of this research was to determine whether Nf1+/− mice have altered seizure susceptibility to the chemical convulsants kainic acid and pilocarpine. Young adult Nf1+/− or WT control (Nf1+/+) mice were injected with either 20 mg/kg kainic acid or scopolamine 1 mg/kg and pilocarpine 300 mg/kg and assessed for various behavioral seizure parameters. Another subset of mice were implanted with intracranial electrodes and injected with 10 mg/kg kainic acid for electrographic seizure testing. Histological analyses were performed one week after kainic acid challenge to assess hippocampal damage. A higher proportion of Nf1+/− mice had behavioral seizures after kainic acid or pilocarpine challenge, with shorter seizure latency, longer seizure duration, and higher Racine scores compared to WT mice. Nf1+/− and WT mice with severe behavioral seizures demonstrated similar levels of hippocampal damage. EEG recordings confirmed decreased seizure latency and longer seizure duration in response to KA in the Nf1+/− group. These data demonstrate increased seizure susceptibility in a mouse model of NF1 and support the use of the Nf1+/− mouse for further investigations into the mechanistic link between NF1 and seizures.