Abstracts

Rationale: Tuberous Sclerosis Complex (TSC) is a genetic neurodevelopmental disorder with an estimated prevalence of one in 6,000 newborns that primarily results from mutation in either TSC1 or TSC2 genes. It is characterized by the formation of benign tumors in many organ systems, epilepsy, intellectual disability, hyperactivity, and autism. When developing possible treatments for TSC, there is a need for a rodent model which has the phenotypes that best represent the symptoms of patients, many of which have epilepsy. However, while a mouse model of TSC1 mutation exists, the human disease resultant from TSC2 mutation has not been adequately modeled in rodents with respect to epilepsy and hyperactivity. Previously we have found that a mouse model with a neuronal deficit of Tsc2 protein, the Tsc2c-del3/- SynICre+ model, exhibits a strong phenotype of hyperactivity. Here for the first time, we describe the epileptic phenotype of the Tsc2KC+ mice demonstrating its utility as a mouse model representative of TSC patients with epilepsy. Methods: Tsc2KC+ mutant (n=10) and control (n=6) mice at 6-7 weeks age were anesthetized using ketamine (100 mg/kg, i.p.) and xylazine (10 mg/kg, i.p.). Two channel wireless telemetry transmitters were implanted intraperitoneally and electrodes were placed supradurally over the left occipital lobe and the right olfactory bulb. Continuous video EEG, core body temperature, and locomotor activity data were collected over a period of 48 hours from the freely-moving animals housed individually in their home cages. An automated seizure detection algorithm was applied to the EEG data for counting seizure events that were also verified by visual inspection. Results: Analyzed over 24 hours, the Tsc2KC+ mutant mice had a significantly higher frequency of seizures in comparison with controls (86.8 ± 21.5 vs 1.3 ± 0.6; p<0.01). Also, the total ictal time per 24 hours in KC+ mutants was significantly longer than the controls (249.8s ± 62.1s vs 3.2s ± 1.6s; p<0.01). Conclusions: We demonstrate that Tsc2KC+ is a robust epileptic phenotype with a high rate of seizure incidence. In future work, we plan to test the effect of acute drug treatment on seizures in this mouse model.