P2Y₆ receptor-dependent microglial phagocytosis of synapses mediates synaptic and memory loss in aging

Aging causes loss of brain synapses and memory, and microglial phagocytosis of synapses may contribute to this loss. Stressed neurons can release the nucleotide UTP, which is rapidly converted into UDP, that in turn activates the P2Y₆ receptor (P2Y₆ R) on the surface of microglia, inducing microglial phagocytosis of neurons. However, whether the activation of P2Y₆ R affects microglial phagocytosis of synapses is unknown. We show here that inactivation of P2Y₆ R decreases microglial phagocytosis of isolated synapses (synaptosomes) and synaptic loss in neuronal-glial co-cultures. In vivo, wild-type mice aged from 4 to 17 months exhibited reduced synaptic density in cortical and hippocampal regions, which correlated with increased internalization of synaptic material within microglia. However, this aging-induced synaptic loss and internalization were absent in P2Y₆ R knockout mice, and these mice also lacked any aging-induced memory loss. Thus, P2Y₆ R appears to mediate aging-induced loss of synapses and memory by increasing microglial phagocytosis of synapses. Consequently, blocking P2Y₆ R has the potential to prevent age-associated memory impairment.