Glial KCNQ K+ channels control neuronal output by regulating GABA release from glia in C. elegans.

KCNQs are voltage-gated K+ channels that control neuronal excitability and are mutated in epilepsy and autism spectrum disorder (ASD). KCNQs have been extensively studied in neurons, but their function in glia is unknown. Using voltage, calcium, and GABA imaging, optogenetics, and behavioral assays, we show here for the first time in Caenorhabditis elegans (C. elegans) that glial KCNQ channels control neuronal excitability by mediating GABA release from glia via regulation of the function of L-type voltage-gated Ca2+ channels. Further, we show that human KCNQ channels have the same role when expressed in nematode glia, underscoring conservation of function across species. Finally, we show that pathogenic loss-of-function and gain-of-function human KCNQ2 mutations alter glia-to-neuron GABA signaling in distinct ways and that the KCNQ channel opener retigabine exerts rescuing effects. This work identifies glial KCNQ channels as key regulators of neuronal excitability via control of GABA release from glia.

Glial regulators of ions and solutes required for specific chemosensory functions in Caenorhabditis elegans.

Glia and accessory cells regulate the microenvironment around neurons and primary sensory cells. However, the impact of specific glial regulators of ions and solutes on functionally diverse primary cells is poorly understood. Here, we systemically investigate the requirement of ion channels and transporters enriched in Caenorhabditis elegans Amsh glia for the function of chemosensory neurons. Although Amsh glia ablated worms show reduced function of ASH, AWC, AWA, and ASE neurons, we show that the loss of glial enriched ion channels and transporters impacts these neurons differently, with nociceptor ASH being the most affected. Furthermore, our analysis underscores the importance of K+, Cl-, and nucleoside homeostasis in the Amphid sensory organ and uncovers the contribution of glial genes implicated in neurological disorders. Our findings build a unique fingerprint of each glial enriched ion channel and transporter and may provide insights into the function of supporting cells of mammalian sensory organs.