TMEM16C is involved in thermoregulation and protects rodent pups from febrile seizures

Abstract

Significance As the most common convulsive disorder in infancy and childhood, affecting 2 to 5% of American children in their first 5 y of life, febrile seizures (FSs) are associated with genetic risk factors, including the Tmem16c (Ano3) gene. Whereas central neuronal hyperexcitability has been implicated in FSs, whether FSs may result from compromised body temperature regulation is unknown. To approach this question, we developed rodent models of FSs associated with deficient thermoregulation, including conditional knockout mice with TMEM16C eliminated from a hypothalamic neuronal population important for maintaining body temperature but not from most of the cortical and hippocampal neurons and sensory neurons. Our findings raise the possibility that impaired homeostatic thermoregulation could contribute to the risk of FSs. Febrile seizures (FSs) are the most common convulsion in infancy and childhood. Considering the limitations of current treatments, it is important to examine the mechanistic cause of FSs. Prompted by a genome-wide association study identifying TMEM16C (also known as ANO3) as a risk factor of FSs, we showed previously that loss of TMEM16C function causes hippocampal neuronal hyperexcitability [Feenstra et al., Nat. Genet. 46, 1274–1282 (2014)]. Our previous study further revealed a reduction in the number of warm-sensitive neurons that increase their action potential firing rate with rising temperature of the brain region harboring these hypothalamic neurons. Whereas central neuronal hyperexcitability has been implicated in FSs, it is unclear whether the maximal temperature reached during fever or the rate of body temperature rise affects FSs. Here we report that mutant rodent pups with TMEM16C eliminated from all or a subset of their central neurons serve as FS models with deficient thermoregulation. Tmem16c knockout (KO) rat pups at postnatal day 10 (P10) are more susceptible to hyperthermia-induced seizures. Moreover, they display a more rapid rise of body temperature upon heat exposure. In addition, conditional knockout (cKO) mouse pups (P11) with TMEM16C deletion from the brain display greater susceptibility of hyperthermia-induced seizures as well as deficiency in thermoregulation. We also found similar phenotypes in P11 cKO mouse pups with TMEM16C deletion from Ptgds-expressing cells, including temperature-sensitive neurons in the preoptic area (POA) of the anterior hypothalamus, the brain region that controls body temperature. These findings suggest that homeostatic thermoregulation plays an important role in FSs.