This abstract has been invited to present during the Investigators Workshop Platform poster session
Rationale: Patients with Dravet syndrome are frequently pharmacoresistant, and current medications act on drug targets that are typically expressed on multiple neuronal subtypes. It is currently unknown whether pharmacologically targeting specific cell types may be a more effective strategy in treating Dravet Syndrome. Retigabine (RTG) is a unique drug which specifically targets channels encoded by Kcnq2-5. Here we ask whether deleting Kcnq2 from neurons (Kcnq2-fl) expressing parvalbumin (PV-Cre) or somatostatin (SOM-Cre) alters the efficacy of retigabine. Methods: Scn1a+/- mice, ages P30-45, were implanted with bilateral frontal and parietal electrodes and then subsequently exposed to closed-loop thermal induction to induce seizures with or without treatment with RTG. Scn1a+/- mice were then crossed with either PV-Cre/Kcnq2-fl or SOM-Cre/Kcnq2-fl mice to specifically remove Kcnq2 from the respective interneuron subtype. Thermal induction experiments with or without RTG were then again performed. Chemogenetic experiments were also performed using inhibitory DREADD (Gi) receptors specifically expressed in parvalbumin-expressing interneurons (PV-INs). Results: Retigabine was effective in reducing thermally-induced seizures in Scn1a+/- mice (saline [n=17]: 35.3% vs RTG [n=18]: 77.8% seizure-free, p=0.015, Mantel-Cox test). Removal of Kcnq2 from both PV-IN and SOM-IN significantly increased spontaneous mortality by P42 (p=0.012 and p=0.049, respectively, Gehan-Breslow-Wilcoxon test). However, RTG had a non-significant trend toward improving seizures in PV-Cre/Kcnq2-fl mice (saline [n=9]: 0.0%, RTG [n=12]: 25.0% seizure free, p=0.066), and no significant effect in SOM-Cre/Kcnq2-fl mice (saline [n=7]: 0.0%, RTG [n=7]: 0.0%, seizure-free, p=0.136). In addition, Scn1a+/-; PV-Cre/Gi-fl mice had no significant difference in susceptibility to thermally-induced seizures between 0.1 mg/kg clozapine (n=19, 0.0% seizure-free), 1 mg/kg clozapine (n=16, 0.0% seizure-free) and saline (n=22, 6.8% seizure-free, p=0.3713, Mantel-Cox test). Conclusions: These results support the hypothesis that the therapeutic effect of RTG in Dravet syndrome mice is independent of its effect on PV-INs. Further work with pharmacological and chemogenetic studies are warranted to test whether specifically targeting somatostatin-expressing interneurons (SOM-INs) may have therapeutic potential in Dravet Syndrome. Funding: Please list any funding that was received in support of this abstract.: NINDS K08 NS096029
.jpg "Alina Sonesra photo")