Abstracts

This abstract has been invited to present during the Broadening Representation Inclusion and Diversity by Growing Equity (BRIDGE) poster session

Rationale: Odors have been used as therapy for illness for millennia, including as treatment of epilepsy. There remains a lack of investigation into the mechanisms by which olfactory and activation of olfactory pathways could alter epilepsy and seizure severity. Our goal was to explore the actions of odorants on mortality and seizures in a Dravet Syndrome mouse model (scn1a^+/- mice), which have spontaneous seizures and high rate of death from sudden unexpected death in epilepsy (SUDEP). We hypothesize that odorants that have actions on olfactory to extended amygdala pathways will decrease SUDEP, potentially through the ability to attenuate neuronal activation in the extended amygdala. In particular, the odorant 2-phenylethanol (2PE, rose odor) is of interest for its ability to block stress induced activation of extended amygdala nuclei (Lee 2022). The amygdala has been implicated as a site important for forebrain control of respiration (Dlouhy 2015, Rhone 2020, Nobis 2018). Thus, exposure to odorants that diminish activation in extended amygdalar regions may be a therapeutic option to prevent SUDEP in this mouse model.

Methods: Dravet syndrome mice (heterozygous scn1a^+/- ) were exposed for at least 8 hours a day to either 2-phenylethanol (2PE), lemon extract, or vehicle odorant in group housed cages. This was repeated daily for 15 days starting at postnatal day 20/21. Mortality in each group was recorded in each group, and seizure frequency was tracked. A subset of 2PE exposed animals had an extended washout period following odorant exposure to continue to determine the long-term effect of odorant exposure on mortality.

Results: Our preliminary results show a strong trend for decreased mortality in the 2PE exposed group (16.1% mortality 2PE (n=31) vs 38.5% mortality in vehicle control (n=26), p=0.06, Barnard’s test). Survival analyses show similar results (p=0.056 Kaplan-Meier curve). The lemon scent exposed animals had a non-significant increase in mortality from preliminary experiments (50% mortality, n=8). Furthermore, in the subset of 2PE exposed mice with an extended washout period (n=15) two subsequent deaths were seen at days outside the typical period of mortality in the scn1a^+/- animals (at P45 and P47). Overall, suggestive that mortality effect is dependent on particular odorants and that this effect is transient.

Conclusions: Our preliminary data support that odorant exposure can decrease mortality in a Dravet Syndrome mouse model, suggesting that more work to determine the mechanism of action and circuitry involved may illuminate new targets and therapies for preventing SUDEP in epilepsy patients.

Funding: This work was supported by the American Epilepsy Society (Junior Investigator Award), Vanderbilt University (Vanderbilt Faculty Research Scholars (VFRS) Award), and the National Center for Advancing Translational Sciences (grant number KL2TRO02245).