Abstracts

Rationale: Rationale
Tuberous sclerosis (TS) is a developmental disorder resulting from the functional inactivation of theTSC1 or TSC2 genes. These genes encode the proteins hamartin and tuberin respectively, and their inactivation results in excessive mammalian target of rapamycin (mTOR) signaling. TS impacts many organ systems and important clinical features of the condition include epilepsy, autism, intellectual disability, and benign tumors. The search for effective treatments for TS would be enhanced by the identification of biomarkers of TS pathology. This would not only help identify those patients at risk for developing TS-associated disorders such as epilepsy, but it could also be useful in trials of candidate therapies. One attractive approach is to find features which are to some extent specific to the EEG from TS patients, and which correlate with neurological dysfunction. In the experiments described here, we examined EEG power in a mouse model of TS.

Methods: Methods
For these studies we used a Tsc1 conditional knockout (Tsc1^GFAPCKO) mouse line in which a GFAP promoter drives the Cre-mediated TSC1 deletion (a generous gift from Dr. Michael Wong, Washington University). Cre-negative littermates were used as controls. Both sexes were used. Mice were implanted with bilateral screw electrodes at 1.5 mm posterior and 1.2 ml lateral to bregma. Following recovery, mice were monitored 24/7 by video/EEG from postnatal (P) 42 to P49 when spontaneous recurrent seizures are well established in this model. EEG signals were filtered at 100 Hz and digitized at 1 kHz. The EEG from 48 recording hours was segmented into 10 sec epochs and power was calculated with Sirenia Seizure Pro software (Pinnacle Technology, Inc.). Power bands were defined as following: total (0.5 - 80 Hz), delta (0.5 – 4 Hz), theta (4 - 8 Hz), alpha (8 – 12 Hz), beta (12 – 30 Hz) and gamma (30 – 80 Hz). For statistics, unpaired t-tests were used to compare the two groups.

Results: Results
Power analysis of the EEGs revealed multiple abnormalities in the Tsc1^GFAPCKO mice compared to controls, consistent with previous studies in this model performed during earlier development stages (P10-P21). The total power was reduced in Tsc1^GFAPCKO compared to wild type mice (p < 0.05). Relative power in the delta band was higher (p < 0.05) and the ratio of theta to delta power was lower in Tsc1^GFAPCKO mice (p < 0.05), primarily due to increased delta activity, as there were no differences in the relative theta power. In both alpha and gamma bands, relative power was lower in the mutant animals (p < 0.01 and p < 0.05)