Microglial P2Y 6 calcium signaling promotes phagocytosis and shapes neuroimmune responses in epileptogenesis.

Microglial calcium signaling is rare in a baseline state but shows strong engagement during early epilepsy development. The mechanism and purpose behind microglial calcium signaling is not known. By developing an in vivo UDP fluorescent sensor, GRAB _UDP1.0 , we discovered that UDP release is a conserved response to seizures and excitotoxicity across brain regions. UDP signals to the microglial P2Y ₆ receptor for broad increases in calcium signaling during epileptogenesis. UDP-P2Y ₆ signaling is necessary for lysosome upregulation across limbic brain regions and enhances production of pro-inflammatory cytokines-TNFα and IL-1β. Failures in lysosome upregulation, observed in P2Y ₆ KO mice, can also be phenocopied by attenuating microglial calcium signaling in Calcium Extruder ("CalEx") mice. In the hippocampus, only microglia with P2Y ₆ expression can perform full neuronal engulfment, which substantially reduces CA3 neuron survival and impairs cognition. Our results demonstrate that calcium activity, driven by UDP-P2Y ₆ signaling, is a signature of phagocytic and pro-inflammatory function in microglia during epileptogenesis.
Competing Interests: Declaration of Interests The authors declare no competing interests.