Abstracts

Rationale: Tuberous sclerosis complex (TSC), which results from heterozygous mutation of the TSC1 or TSC2 genes, commonly presents with epilepsy, autism spectrum disorder (ASD), and other cognitive, behavioral, and psychiatric manifestations. In contrast, while mice with heterozygous knockout of the Tsc2 gene (Tsc2+/- mice) have been found to have ASD-like social behaviors, deficits in learning and memory, and increased sensitivity to convulsive agents, they have not been previously reported to exhibit spontaneous recurrent seizures. In the current study, we performed prolonged video EEG monitoring of young juvenile and adult Tsc2+/- mice to assess for the presence or absence of clinical and electrographic seizures.  Methods: Tsc2+/- mice (B6;129S4-Tsc2tm1Djk/J, #004686) were obtained from Jackson Labs and the colony developed through mating of Tsc2 heterozygous mice with wild type mice of the same background. Video EEG monitoring was performed in male and female young juvenile (P13-16) and adult (1-11 months) Tsc2+/- mice and their wild type littermates as per our published protocols. Recordings in young mice consisted of 6 to 8 one-hour sessions over a period of two days, allowing both wake and sleep cycles to be captured while limiting time away from the mother. Recordings in adult mice were performed continuously for a period of 10 to 23 days (average 14 days). EEG tracings and videos were reviewed by investigators blinded to genotype. Results: No clinical or electrographic seizures were recorded in young juvenile (P13-16) Tsc2+/- mice (n=10) or their wild type littermates (n=8). However, electroclinical seizures were seen in a subset of adult Tsc2+/- mice. Of 16 adult Tsc2+/- mice undergoing video EEG monitoring, 4 (25%) had spontaneous recurrent seizures at a rate of 0.4 to 3 seizures per day. Some seizures were generalized tonic-clonic in character, consisting of an initial tonic phase of low amplitude, high frequency spike discharges, followed by a clonic phase of repetitive bursts of spikes. Other seizures were less severe, associated with tail raising, rearing and forearm clonus. Average seizure duration for each animal was 28 to 32 seconds and was associated with postictal depression. One animal died during a seizure. No seizures were recorded in wild type littermates (n=14). Conclusions: In addition to their known behavioral, learning, and memory deficits, a subset of adult heterozygous Tsc2+/- mice experience recurrent spontaneous seizures, similar to patients with TSC. These seizures were relatively infrequent and brief, and were not seen during routine handling of the animals. Studies are ongoing to assess structural and functional brain characteristics of Tsc2+/- mice with versus without spontaneous seizures. This phenotype should also be considered as a potential source of variability in studies of learning and behavior in Tsc2+/- mice. Funding: NIH grant R01 MH110448 to LAJ.