Abstracts

Rationale: Neurofibromatosis type 1 (NF1) is the most common form of the neurocutaneous disorder, affecting up to 1 in 2000 individuals. Rates of epilepsy in NF1 patients have been reported as high as 14%, as compared to approximately 1% of the general population. In some cases the seizures appear to be clearly related to an intracranial lesion, however some studies report up to 50% of NF1 patients with epilepsy have no obvious epileptogenic lesion. This suggests that altered levels of neurofibromin, a tumor suppressor gene, may predispose individuals with NF1 to seizures. The NF1^+/- mouse model has been used extensively in investigations of many aspects of the disorder, such as tumors and cognitive dysfunction, but there have been no previous studies on whether this gene mutation affects seizure susceptibility. Methods: Young adult NF1^+/- and wild-type (WT) mice on a C57BL/6J background were used to determine NF1-related alterations in seizure susceptibility. Altered susceptibility to chemical convulsants was tested in separate groups of NF1^+/- and WT mice via intraperitoneal administration of 20 mg/kg kainic acid (KA) or 300 mg/kg pilocarpine. Mice were then monitored for behavioral seizure activity. A separate group of mice were implanted with intracranial electrodes for rapid hippocampal kindling and subsequent monitoring for interictal epileptiform abnormalities. Results: NF1^+/- mice demonstrated increased seizure susceptibility to both KA and pilocarpine challenge compared with WT mice. After the administration of 20 mg/kg KA, 100% of NF1^+/- mice experienced behavioral seizures (n=10) as compared to 40% of WT mice (n=10). After the administration of 300 mg/kg pilocarpine, 100% of NF1^+/- mice experienced behavioral seizures (n=10) as compared to 30% of WT mice (n=9). NF1^+/- mice had a shorter average seizure latency, an increased average seizure intensity, an increased average seizure duration, and an increased average maximum seizure intensity after challenge with either KA or pilocarpine as compared to the WT group (all p<0.01). Mortality rates were also higher in the NF1^+/- mice. After rapid hippocampal kindling a significant difference in kindling rate was not found between groups (n=10 per group). However in looking at only mice that achieved stage 4 or 5 seizure after rapid kindling, NF1^+/- mice (n=7) did have more interictal hippocampal spikes as compared to the WT group (n=6). Conclusions: The NF1^+/- mouse model has provided great insights into mechanisms surrounding many symptoms of the disorder. For the first time we have demonstrated increased seizure susceptibility in the NF1^+/- mouse. These data suggest that the genetic mutation itself may in part be responsible for the increased seizure susceptibility reported in some patients with NF1, and support the use of this model for further investigations into the mechanistic link between NF1 and seizures and epilepsy. Funding: This work was supported by funds from the Canadian Institutes of Health Research (AYR), the Toronto General and Western Hospital Foundation (AYR), the Natural Science and Engineering Research Council of Canada (LZ), and the Epilepsy Research Program of the Ontario Brain Institute (LZ).