Glial Ca2+ Signaling Links Endocytosis to K+ Buffering around Neuronal Somas to Regulate Excitability

Glial-neuronal signaling at synapses is widely studied, but how glia interact with neuronal somas to regulate neuronal function is unclear. Drosophila cortex glia are restricted to brain regions devoid of synapses, providing an opportunity to characterize interactions with neuronal somas. Mutations in the cortex glial NCKXzydeco elevate basal Ca2+, predisposing animals to seizures. To determine how cortex glial Ca2+ signaling controls neuronal excitability, we performed an in vivo modifier screen of the NCKXzydeco seizure phenotype. We show that elevation of glial Ca2+ causes hyperactivation of calcineurin-dependent endocytosis and accumulation of early endosomes. Knockdown of sandman, a K2P channel, recapitulates NCKXzydeco seizures. In addition, restoring glial K+ buffering by ectopically expressing a leak K+ channel abolishes NCKXzydeco seizures. These data provide an unexpected link between glial Ca2+ signaling and the more well-known roles of glia in K+ buffering as a key mechanism for regulating neuronal excitability.