The Heat Sensing Trpv1 Receptor Is Not a Viable Anticonvulsant Drug Target in the Scn1a+/− Mouse Model of Dravet Syndrome

Cannabidiol has been approved for the treatment of drug-resistant childhood epilepsies including Dravet syndrome (DS). Although the mechanism of anticonvulsant action of cannabidiol is unknown, emerging data suggests involvement of the transient receptor potential cation channel subfamily V member 1 (Trpv1). Pharmacological and genetic studies in conventional seizure models suggest Trpv1 is a novel anticonvulsant target. However, whether targeting Trpv1 is anticonvulsant in animal models of drug-resistant epilepsies is not known. Thus, we examined whether Trpv1 affects the epilepsy phenotype of the F1.Scn1a+/−mouse model of DS. We found that corticalTrpv1mRNA expression was increased in seizure susceptible F1.Scn1a+/−mice with a hybrid genetic background compared to seizure resistant 129.Scn1a+/−mice isogenic on 129S6/SvEvTac background, suggestingTrpv1could be a genetic modifier. Previous studies show functional loss of Trpv1 is anticonvulsant. However, Trpv1 selective antagonist SB-705498 did not affect hyperthermia-induced seizure threshold, frequency of spontaneous seizures or survival of F1.Scn1a+/−mice. Surprisingly,Trpv1deletion had both pro- and anti-seizure effects.Trpv1deletion did not affect hyperthermia-induced seizure temperature thresholds of F1.Scn1a+/−;Trpv1+/−at P14-16 but was proconvulsant at P18 as it reduced seizure temperature thresholds. Conversely,Trpv1deletion did not alter the frequency of spontaneous seizures but reduced their severity. These results suggest thatTrpv1is a modest genetic modifier of spontaneous seizure severity in the F1.Scn1a+/−model of DS. However, the opposing pro- and anti-seizure effects ofTrpv1deletion and the lack of effects of Trpv1 inhibition suggest that Trpv1 is unlikely a viable anticonvulsant drug target in DS.