Glial KCNQ K+ Channels Control Neuronal Output by Regulating GABA Release from Glia in C. elegans

KCNQ channels are voltage-gated K⁺ channels that are evolutionarily conserved across species. Among the five genes responsible for encoding KCNQ channels in humans, four are expressed in the nervous system. KCNQs display a low threshold of activation and non-inactivating current, features that make these channels good regulators of cellular excitability. In the nervous system, KCNQ channels are expressed in neurons, where they regulate neuronal excitability. Indeed, mutations in KCNQ channels have been associated with neuropsychiatric conditions such as Self-Limited Neonatal Epilepsy, Developmental and Epileptic Encephalopathy, and Autism Spectrum Disorder (ASD) in children. However, KCNQ channels are also expressed in glial cells, and the function of KCNQ channels in glia remains unclear. Previous work from the Bianchi’s Lab has shown that the C. elegans KCNQ homolog channel kqt-2 is needed in amphid sheath glia for the nematode response to 1-octanol. Strikingly, at a cellular level loss of glial kqt-2 leads to reduction of amphid sheath glia activity but to increase in neuronal excitability. Here, I show that glial KCNQ channels are needed in glia to mediate GABA release from these cells upon stimulation with 1-octanol. Further, I show that KCNQs are needed in glia to maintain a membrane potential that is favorable for the activity of voltage-gated Ca²⁺ channel egl-19 and, therefore, for intracellular Ca²⁺ increase in glia. Finally, I found that pathogenic KCNQ mutations expressed in glia affect the resting membrane potential and post-stimulus repolarization in these cells, as well as GABA release, suggesting that glial KCNQ channels contribute to the pathogenesis of KCNQ associated disorders. These data suggest glial KCNQ channels are potential novel targets for the treatment of KCNQ-associated conditions.