Microglial MERTK eliminates phosphatidylserine-displaying inhibitory post-synapses

Glia contribute to synapse elimination through phagocytosis in the central nervous system. Despite the important roles of this process in development and neurological disorders, the identity and regulation of the eat-me signal that initiates glia-mediated phagocytosis of synapses has remained incompletely understood. Here, we generated conditional knockout mice with neuronal-specific deletion of the flippase chaperone Cdc50a, to induce stable exposure of phosphatidylserine, a well-known eat-me signal for apoptotic cells, on the neuronal outer membrane. Surprisingly, acute Cdc50a deletion in mature neurons causes preferential phosphatidylserine exposure in neuronal somas and specific loss of inhibitory post-synapses without effects on other synapses, resulting in abnormal excitability and seizures. Ablation of microglia or the deletion of microglial phagocytic receptor Mertk prevents the loss of inhibitory post-synapses and the seizure phenotype, indicating that microglial phagocytosis is responsible for inhibitory post-synapse elimination. Moreover, we found that phosphatidylserine is used for microglia-mediated pruning of inhibitory post-synapses in normal brains, suggesting that phosphatidylserine serves as a general eat-me signal for inhibitory post-synapse elimination.

Automated summary

Phosphatidylserine plays a role in promoting glia-mediated synapse elimination in the central nervous system, leading to the specific loss of inhibitory post-synapses and seizures in mature neurons; Microglial phagocytosis is responsible for inhibitory post-synapse elimination, with phosphatidylserine serving as a general eat-me signal.