Abstracts

Rationale: Hyperventilation triggers seizures in most patients with absence epilepsy. To understand the physiological parameters that underlie hyperventilation-provoked absence seizures we developed rat and mouse models that recapitulate the predictable human seizure response. We now use these models to both (1) resolve the cellular mechanisms that contribute to hyperventilation-provoked seizures, and (2) resolve neural circuits that initiate and propagate absence seizures.

Methods: EEG recordings, coupled with plethysmography, were performed in seizure-prone rats (WAG/Rij) and mice (Gria4 mutant). We also performed multielectrode, silicone probe recordings in head-fixed Gria4 mutants. Gas exchanges and optogenetics were used to activate respiratory centers to drive hyperventilation.

Results: Absence seizures appear to be primarily sensitive to the respiratory alkalosis that accompanies hyperventilation. In both rodent models, hypoxia-induced hyperventilation provokes a burst of spike-wave discharges (SWDs), electrographic correlates of absence seizures, that is also associated with an alkalization of arterial pH. Arterial alkalization is expected as CO₂, an acidic molecule, is excessively expired during hyperventilation. Consistent with the hypothesis that SWDs are specifically provoked by alkalosis, supplementing hypoxic conditions with high CO₂ suppresses the SWD response; high CO₂ alone is also sufficient to reduce SWDs in the rodents. Activity-dependent labeling approaches (i.e., cFos) suggest that hyperventilation activates neurons in the intralaminar thalamic nuclei to provoke SWD-generating neural circuits.

Using multielectrode silicone recording probes in head-fixed Gria4 mutants, we are leveraging the predictability of hyperventilation-provoked SWDs to identify neural circuit activity patterns that precipitate seizures. Our recordings show that spontaneous (i.e., during normal breathing conditions) and hyperventilation-provoked SWDs follow a stereotyped temporal progression of activity. Also, preliminary recordings indicate that the midline thalamic nuclei, including some intralaminar nuclei, produce SWDs before the laterally-situated sensory nuclei.

Conclusions: Collectively, our data support a model wherein pH sensitive neurons of midline thalamic structures precipitate hyperventilation-provoked absence seizures.

Funding: Please list any funding that was received in support of this abstract.: NIH R01NS099586.