Abstracts

Rationale: Absence epilepsy can be aggravated by frequently used AEDs such as carbamazepine and vigabatrin. Therefore, a biomarker which could predict whether seizures may get better or worse, shortly after starting an AED, would significantly improve drug development and patient care. Cortical parvalbumin-expressing interneurons have been associated with the generation of gamma (30-100 Hz) oscillations, and dysfunction in these interneurons has been implicated in both the stargazer and tottering mouse models of absence epilepsy. In this study, we evaluate the potential for using gamma power as a biomarker for drug response in absence epilepsy.Methods: Interictal EEG power between 2-300 Hz and total seizure duration were analyzed before and after intraperitoneal drug administration in stargazer and tottering mutants. Mice were recorded at 2 kHz with WT littermates and saline administration used as controls. Comparisons were made with a 2-way repeated measures ANOVA with correction for multiple comparisons.Results: There is a significant augmentation in the baseline absolute power across the 14-49 Hz frequency band in stargazer mice (n=12) compared to both tottering (n=9) and WT mice (n=10; p<0.05). NMDA receptor blockade with 0.5 mg/kg MK-801 causes seizure exacerbation and a reduction of the augmented beta/gamma frequency band to WT levels in stargazer mice (n=5, p<0.05), whereas MK-801 significantly reduces seizures and increases relative power within the gamma band in tottering mice (n=5, p<0.05). Ethosuximide (200 mg/kg) and 4-aminopyridine (2.5 mg/kg) reduce seizure activity in both lines (n=5 in each line) and cause an increase relative power within the gamma-frequency range (p<0.05). Altogether, including 10 mg/kg CPP, 20 mg/kg carbamazepine, and 10 mg/kg flupirtine in both models of absence epilepsy (n=5 in each group), there is an inverse correlation between change in seizure duration and peak change in normalized relative gamma power (r2=0.62).Conclusions: CONCLUSIONS: Gamma power is augmented in stargazer mice, likely due to an NMDA-receptor mediated compensatory mechanism given normalization of gamma power and seizure exacerbation with NMDA receptor blockade. In addition, change in relative gamma power during the interictal state may serve as a biomarker for AED efficacy. Further studies with more AEDs and on patients with absence epilepsy are necessary to determine the generalizability of these results.