Mutation of a NCKX Eliminates Glial Microdomain Calcium Oscillations and Enhances Seizure Susceptibility

Glia exhibit spontaneous and activity-dependent fluctuations in intracellular Ca2+, yet it is unclear whether glial Ca2+oscillations are required during neuronal signaling. Somatic glial Ca2+waves are primarily mediated by the release of intracellular Ca2+stores, and their relative importance in normal brain physiology has been disputed. Recently, near-membrane microdomain Ca2+transients were identified in fine astrocytic processes and found to arise via an intracellular store-independent process. Here, we describe the identification of rapid, near-membrane Ca2+oscillations inDrosophilacortex glia of the CNS. In a screen for temperature-sensitive conditional seizure mutants, we identified a glial-specific Na+/Ca2+, K+exchanger (zydeco) that is required for microdomain Ca2+oscillatory activity. We found thatzydecomutant animals exhibit increased susceptibility to seizures in response to a variety of environmental stimuli, and thatzydecois required acutely in cortex glia to regulate seizure susceptibility. We also found that glial expression of calmodulin is required for stress-induced seizures inzydecomutants, suggesting a Ca2+/calmodulin-dependent glial signaling pathway underlies glial–neuronal communication. These studies demonstrate that microdomain glial Ca2+oscillations require NCKX-mediated plasma membrane Ca2+flux, and that acute dysregulation of glial Ca2+signaling triggers seizures.