Glial Ca²⁺signaling links endocytosis to K⁺ buffering around neuronal somas to regulate excitability.

Abstract

Glial-neuronal signaling at synapses is widely studied, but how glia interact with neuronal somas to regulate their activity is unclear. <i>Drosophila</i> cortex glia are restricted to brain regions devoid of synapses, providing an opportunity to characterize interactions with neuronal somas. Mutations in the cortex glial <i>NCKX^zydeco</i> elevate basal Ca²⁺, predisposing animals to seizure-like behavior. To determine how cortex glial Ca²⁺ signaling controls neuronal excitability, we performed an in vivo modifier screen of the <i>NCKX^zydeco</i> seizure phenotype. We show that elevation of glial Ca²⁺ causes hyperactivation of calcineurin-dependent endocytosis and accumulation of early endosomes. Knockdown of sandman, a K_2P channel, recapitulates <i>NCKX^zydeco</i> seizures. Indeed, sandman expression on cortex glial membranes is substantially reduced in <i>NCKX^zydeco</i> mutants, indicating enhanced internalization of sandman predisposes animals to seizures. These data provide an unexpected link between glial Ca²⁺ signaling and the well-known role of glia in K⁺ buffering as a key mechanism for regulating neuronal excitability.