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The Nutshell<br>Overactive Neurons Cause Excessive Sweating<br>Identification of gene variants that affect the activity of neuronal sodium channels could help develop targeted therapies for patients suffering from excessive sweating.<br>Written byShelby Bradford, PhDShelby Bradford, PhD

Shelby is an Assistant Editor for The Scientist. She earned her PhD from West Virginia University in immunology and microbiology and completed an AAAS Mass Media fellowship.<br>View Full Profile<br>Learn about our Editorial Policies.

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A gene variant in a sodium channel caused excessive sweating in mice.<br>Image credit:&copy;iStock.com, Cunaplus_M.Faba

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Sweating is a normal, although sometimes unpleasant, part of being human. For people with primary idiopathic hyperhidrosis (PIH), though, excessive sweating can impede their quality of life. Despite affecting up to five percent of people, though, scientists don’t fully understand the mechanisms behind this overactive salty secretion.<br>Researchers have found that some patients have alterations to their sweat glands’ morphology or function, possibly contributing to the extra sweating.1 But for people who sweat excessively despite having normal looking sweat glands, scientists suspect that the cause could be hyperactive sympathetic neurons.2<br>In a study published recently in Science Advances, researchers dug into the genetic sequences of 32 families with confirmed PIH to find possible sources of overactive sweat responses. They identified a lead candidate in SCN10A, a gene encoding a sodium channel in sympathetic neurons and discovered that introducing it into mice reproduced the extra sweating phenotype of PIH individuals.3 They showed how their mouse model of PIH could be used to explore new treatment options for patients.<br>“For decades, hyperhidrosis has largely been viewed as a disorder of the sweat glands. Our findings show that, for some patients, the problem actually begins in the nerves that control sweating, providing a biological explanation for the condition and a potential pathway to more effective treatments,” said Malcolm Brock, a surgeon at Johns Hopkins University who sees patients with PIH and study author, in a press release.<br>Continue reading below...<br>Like this story? Sign up for FREE Cell Biology updates:<br>Latest science news storiesTopic-tailored resources and eventsCustomized newsletter content<br>Subscribe

The researchers completed whole exome sequencing of individuals from their PIH cohort and identified 398 protein-coding genes with variations that were enriched in these patients. Cross-referencing these to genes involved in sodium channels, which are important for neuron activation, or other neuronal machinery, they found SCN10A, which encodes for the voltage-gated sodium channel (Nav) 1.8. The team further identified a specific variant associated with PIH in this gene.<br>The team introduced this mutation into human neurons in cell culture and studied its effects on the cells’ electrophysiology. They found that the variant NAv1.8 had twice the amount of current flow compared to the wild type channel, signifying more activity. They also observed that its activation threshold was shifted so that the cells responded to lower amounts of stimulus.<br>Seeing that the PIH variant in NAv1.8 affected neuron activity, the researchers introduced this same mutation into mice using CRISPR-Cas9. Sympathetic neurons isolated from wild type and NAv1.8 mutant mice replicated the respective electrophysiology observed in humans, confirming that this mutation affected the mouse nervous system comparably to humans.<br>Next, to study the effect of this sodium channel mutation on sweat in vivo, the researchers modified an existing assay to induce sweating with the topical application of iodine and starch. Unlike in humans, mice only have sweat glands on their footpads, so the study was restricted to this body area.<br>Two minutes after applying their treatment, the researchers imaged the footpads and measured the total area of sweat. They found that mice with the NAv1.8 variant produced more sweat compared to wild type mice. To confirm that this channel was responsible for the sweat response, they used a channel-specific inhibitor in their mutant mice and also separately knocked out NAv1.8 in another group of mice. In both of these conditions, the sweat response was comparable to that in wild type animals, confirming the role of the variant NAv1.8 in excessive sweating.<br>Finally, the researchers explored currently available clinical therapies for people with PIH in their variant NAv1.8 mouse model. They treated mice with either aluminum chloride, glycopyrrolate, oxybutynin, and guanfacine. Although each has a different mechanism of action, all four therapies reduced sweating in the mutant mice. The...