Abstracts

Rationale: Neurofibromatosis type 1 (NF1), an autosomal dominant neurocuteanous disorder, is associated with higher rates of epilepsy compared to the general population. While many patients with NF1 have intracranial lesions, it is possible that the genetic mutation itself contributes to the higher rate of epilepsy, as up to 50% of NF1 patients with epilepsy are non-lesional. However, there have been no preclinical studies investigating seizures and epilepsy in NF1. We have performed studies in Nf1+/- mice to investigate alterations in electrical kindling rates and epileptogenesis in both hippocampal and neocortical brain regions. Methods: Young male or female adult Nf1+/- or wild-type (WT) mice were implanted with electrodes for extended hippocampal kindling or classic neocortical kindling paradigms (n=10/sex/group). Baseline EEG was recorded for up to 48 hours prior to kindling, followed by determination of afterdischarge thresholds (ADTs). Neocortical kindling was performed for 40 stimulation sessions, and hippocampal kindling was performed until mice exhibited spontaneous seizures, or until a maximum of 120 stimulations. Results: Approximately 25% of Nf1+/- mice had spontaneous seizures at baseline. There were no differences in hippocampal kindling parameters between groups. However, Nf1+/- mice had lower neocortical ADTs (79.41 +/- 6.55 vs 102.66 +/-8.58, p<0.05) and faster kindling rates, reaching first Racine stage 5 seizure after 11 +/-1 vs. 20 +/- 3 stimulations (p<0.05). No sex differences were found. Conclusions: These results suggest the genetic mutation in NF1 leads to regional variability in seizure predisposition and at least contributes to seizures in non-lesional NF1 patients with epilepsy. Future molecular studies will help elucidate the mechanisms contributing to regional differences in neuro-excitability. Funding: Toronto General and Western Hospital Foundation