RRC ID 65623
Author Wang TA, Chen C, Huang F, Feng S, Tien J, Braz JM, Basbaum AI, Jan YN, Jan LY.
Title TMEM16C is involved in thermoregulation and protects rodent pups from febrile seizures.
Journal Proc Natl Acad Sci U S A
Abstract 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.
Volume 118(20)
Published 2021-5-18
DOI 10.1073/pnas.2023342118
PII 2023342118
PMID 33972431
PMC PMC8157992
MeSH Action Potentials / physiology Animals Animals, Newborn Body Temperature / drug effects Body Temperature / physiology Body Temperature Regulation / genetics* Chloride Channels / deficiency Chloride Channels / genetics* Female Fever / chemically induced Fever / genetics* Fever / metabolism Fever / physiopathology Gene Expression Hippocampus / metabolism Hippocampus / physiopathology Hyperthermia / genetics* Hyperthermia / metabolism Hyperthermia / physiopathology Kainic Acid / administration & dosage Male Mice Mice, Knockout Neurons / metabolism Neurons / pathology Preoptic Area / metabolism* Preoptic Area / physiopathology Protein Isoforms / deficiency Protein Isoforms / genetics Rats Seizures, Febrile / chemically induced Seizures, Febrile / genetics* Seizures, Febrile / metabolism Seizures, Febrile / physiopathology
IF 9.412
Mice RBRC01868