Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia

EMBO J. 2020 Aug 17;39(16):e105380. doi: 10.15252/embj.2020105380. Epub 2020 Jul 13.


Neuronal circuit assembly requires the fine balance between synapse formation and elimination. Microglia, through the elimination of supernumerary synapses, have an established role in this process. While the microglial receptor TREM2 and the soluble complement proteins C1q and C3 are recognized as key players, the neuronal molecular components that specify synapses to be eliminated are still undefined. Here, we show that exposed phosphatidylserine (PS) represents a neuronal "eat-me" signal involved in microglial-mediated pruning. In hippocampal neuron and microglia co-cultures, synapse elimination can be partially prevented by blocking accessibility of exposed PS using Annexin V or through microglial loss of TREM2. In vivo, PS exposure at both hippocampal and retinogeniculate synapses and engulfment of PS-labeled material by microglia occurs during established developmental periods of microglial-mediated synapse elimination. Mice deficient in C1q, which fail to properly refine retinogeniculate connections, have elevated presynaptic PS exposure and reduced PS engulfment by microglia. These data provide mechanistic insight into microglial-mediated synapse pruning and identify a novel role of developmentally regulated neuronal PS exposure that is common among developing brain structures.

Keywords: C1q; TREM2; microglia; phosphatidylserine; synapse pruning.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Coculture Techniques
  • Complement C1q / genetics
  • Complement C1q / metabolism
  • Complement C3 / genetics
  • Complement C3 / metabolism
  • Hippocampus / metabolism*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Knockout
  • Microglia / metabolism*
  • Neurons / metabolism*
  • Phosphatidylserines / genetics
  • Phosphatidylserines / metabolism*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism
  • Synapses / genetics
  • Synapses / metabolism*


  • Complement C3
  • Membrane Glycoproteins
  • Phosphatidylserines
  • Receptors, Immunologic
  • Trem2 protein, mouse
  • Complement C1q