CDC50A dependent phosphatidylserine exposure induces inhibitory post-synapse elimination by microglia

Glia contribute to synapse elimination through phagocytosis in the central nervous system. Despite important roles during development and neurological disorders, the “eat-me” signal that initiates glia-mediated phagocytosis of synapses remains largely elusive. Here, by generating inducible conditional knockout mice of Cdc50a , we induced stable exposure of phosphatidylserine in the neuronal outer membrane. Surprisingly, acute Cdc50a deletion in neurons causes specific loss of inhibitory post-synapses without affecting other synapses, thereby generating excessive excitability with appearance of seizure. Ablating microglia or deleting microglial Mertk rescues the loss of inhibitory post-synapses, indicating that microglial phagocytosis is responsible for inhibitory post-synapse elimination. Moreover, inhibitory post-synapses in normal juvenile brains also use phosphatidylserine for synapse pruning by microglia, suggesting that phosphatidylserine may serve as a general “eat-me” signal for inhibitory post-synapse elimination. One Sentence Summary Cdc50a dependent phosphatidylserine exposure functions as an “eat-me” signal for microglia-dependent inhibitory post-synapse elimination