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

Glial-neuronal signaling at synapses is widely appreciated, but how glia interact with neuronal cell bodies is less clear. Drosophila cortex glia are restricted to brain regions devoid of synapses, providing an opportunity to characterize interactions between glia and neuronal somas. Mutations in the cortex glial NCKX exchanger zydeco abolish microdomain Ca2+ oscillatory activity and elevate glial Ca2+, predisposing animals to seizures. To determine how cortex glial Ca2+ signaling controls neuronal excitability, an in vivo modifier screen for the NCKXzydeco seizure phenotype was performed. Our results indicate elevation of glial Ca2+ causes hyperactivation of calcineurin-dependent endocytosis and accumulation of early endosomes. Knockdown of sandman, a K2P channel, recapitulates NCKXzydeco seizures. Restoring glial K+ buffering by overexpressing a leak K+ channel rescues zydeco seizures. These findings indicate cortex glial Ca2+ couples to K+ buffering through calcineurin regulated endo-exocytotic balance and K2P channel expression to modulate neuronal excitability.