P2Y6 Receptor-Dependent Microglial Phagocytosis of Synapses during Development Regulates Synapse Density and Memory

During brain development, excess synapses are pruned (i.e., removed), in part by microglial phagocytosis, and dysregulated synaptic pruning can lead to behavioral deficits. The P2Y(6) receptor (P2Y(6)R) is known to regulate microglial phagocytosis of neurons, and to regulate microglial phagocytosis of synapses in cell culture and in vivo during aging. However, currently it is unknown whether P2Y(6)R regulates synaptic pruning during development. Here, we show that P2Y(6)R KO mice of both sexes had strongly reduced microglial internalization of synaptic material, measured as Vglut1 within CD68-staining lysosomes of microglia at postnatal day 30 (P30), suggesting reduced microglial phagocytosis of synapses. Consistent with this, we found an increased density of synapses in the somatosensory cortex and the CA3 region and dentate gyrus of the hippocampus at P30. We also show that adult P2Y(6)R KO mice have impaired short- and long-term spatial memory and impaired short- and long-term recognition memory compared with WT mice, as measured by novel location recognition, novel object recognition, and Y-maze memory tests. Overall, this indicates that P2Y(6)R regulates microglial phagocytosis of synapses during development, and this contributes to memory capacity.