The voltage-gated sodium channel NaV1.1 has emerged as a possible candidate in gustatory signal transmission following the clinical observation that pediatric patients with Dravet syndrome (DS), an epileptic channelopathy resulting from NaV1.1 haploinsufficiency, demonstrate an indifference or aversion to sweet foods ? a highly unusual finding in children. RNA-seq transcriptomic data shows that NaV1.1 is expressed in subsets of ganglion cells thought to transmit particular taste qualities, including sweet. My preliminary behavioral and electrophysiological studies also suggest that NaV1.1 may mediate sweet taste signal transmission, both in an acute, i.e. pharmacological block, mouse model as well as in a genetic model of NaV1.1 haploinsufficiency. In this proposal, three different mouse models ? one acute and two genetic ? will be assessed on peripheral gustatory deficits (Aim 1) and behavioral effects (Aim 2) due to Nav1.1 dysfunction. This study is innovative because our preliminary data suggest that 1) a single type of sodium channel may differentially impact transmission of particular taste qualities, and 2) gustatory function may serve as a surrogate measure for NaV1.1 function. The latter would be particularly useful for assessing phenotype severity in Dravet patients, which as of yet does not have a robust biomarker to use in assessment.
A majority of pediatric patients with Dravet syndrome ? a genetic epileptic encephalopathy resulting from haploinsufficiency of the voltage-gated sodium channel NaV1.1 ? are indifferent to or dislike sweet-tasting foods, a highly unusual finding in a pediatric population. The proposed work investigates the role of NaV1.1 in the transmission of gustatory signals with particular regard to its role in mediating sweet taste. The role of NaV1.1 in neural activity and taste-guided behaviors will be assessed after pharmacological blockade or genetically-induced haploinsufficiency of this channel.
