Abstracts

Rationale: Seizures can act both locally and remotely to alter nervous system function. When seizures propagate beyond their sites of origin, they can have far-reaching effects that lead to irregularities in cardiorespiratory function and impaired consciousness, in some cases culminating in death. Accumulating evidence points to peri-ictal breathing impairment involving serotonergic respiratory regulation as a mechanism underlying sudden unexpected death in epilepsy (SUDEP). Methods: Multi-unit and juxtacellular recordings of midbrain and medullary raphe nuclei were performed in an anesthetized rat model of limbic seizures to study peri-ictal function of serotonergic neurons. Respiratory function was recorded using a method of a head-out-plethysmography. Neurons juxtacellularly recorded were labeled with neurobiotin for histologic recovery and serotonergic neurons were identified using anti-Tryptophan hydroxylase (TpOH) monoclonal antibodies. Results: Decreases in respiratory rate, tidal volume and ventilation were observed during ictal and post-ictal periods, with concomitant decreased neuronal firing in the medullary and midbrain raphe nuclei. Slow wave activities in the frontal cortex indicated depressed cortical activity during and after seizures as well. Preliminary data from single unit activity measurements also suggests specific depression of serotonergic neuron firing rates during partial seizures. Conclusions: These results suggest that seizures propagate to inhibitory circuits suppressing ascending arousal systems and descending respiratory regulation networks, thus impairing physiological pathways for maintaining consciousness and stimulating of respiration. This work is building toward a robust understanding of the mechanistic underpinnings of SUDEP, with possible implications for therapeutic intervention on behalf of patients at risk for epilepsy-associated mortality.