The Drosophila ERG channel seizure plays a role in the neuronal homeostatic stress response

Abstract

Neuronal physiology is particularly sensitive to acute stressors that affect excitability, many of which can trigger seizures and epilepsies. Although intrinsic neuronal homeostasis plays an important role in maintaining overall nervous system robustness and its resistance to stressors, the specific genetic and molecular mechanisms that underlie these processes are not well understood. Here we used a reverse genetic approach in Drosophila to test the hypothesis that specific voltage-gated ion channels contribute to neuronal homeostasis, robustness, and stress resistance. We found that the activity of the voltage-gated potassium channel seizure (sei), an ortholog of the mammalian ERG channel family, is essential for protecting flies from acute heat-induced seizures. Although sei is broadly expressed in the nervous system, our data indicate that its impact on the organismal robustness to acute environmental stress is primarily mediated via its action in excitatory neurons, the octopaminergic system, as well as glia. Furthermore, our studies suggest that human mutations in the human ERG channel (hERG), which have been primarily implicated in the cardiac Long QT Syndrome (LQTS), may also contribute to the high incidence of seizures in LQTS patients via a cardiovascular-independent neurogenic pathway.\n\nAuthor SummaryNeurons are extremely sensitive to diverse environmental stressors, including rapid changes in the ambient temperature. To buffer stress, all animals have evolved diverse physiological mechanisms to protect neuronal activity from acute and chronic stressors, and failures of these safeguards often lead to hyperexcitability, episodic seizures, and chronic epilepsy. Although seizures and related syndromes are common, their underlying molecular and genetic factors, and their interactions with environmental triggers, remain mostly unknown. Here, we show that in the fruit fly, mutations in the ERG voltage-gated potassium channel seizure (sei), an ortholog of the human hERG channel that has been previously implicated in the cardiac Long-QT syndrome, could also increase seizure susceptibility. We demonstrate that in addition to its cardiac expression, the sei channel is broadly expressed in the nervous system, specifically localized to axonal projections, and is specifically required in excitatory and modulatory neurons, as well as non-neuronal glia for maintaining organismal resistance to heat-induced seizures. Thus, our work suggests that the previously reported increase in seizure susceptibility in individuals with mutations in hERG are likely directly related to its neuronal action, independent of its cardiac function.