IRCCS Humanitas Research Hospital & Humanitas University
Published July 13, 2020 | Version v1
Dataset Open

Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia

Authors/Creators

  • 1. F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Boston, MA, USA; AND Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 2. Humanitas Clinical and Research Center - IRCCS, Rozzano (MI), Italy; AND Humanitas University, Pieve Emanuele (MI), Italy.
  • 3. Humanitas Clinical and Research Center - IRCCS, Rozzano (MI), Italy.
  • 4. F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Boston, MA, USA.
  • 5. Max Planck Institute for Biophysical Chemistry, Göttingen, Germany; AND Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany.
  • 6. Humanitas University, Pieve Emanuele (MI), Italy.
  • 7. Max Planck Institute for Biophysical Chemistry, Göttingen, Germany; AND University of Göttingen, Göttingen, Germany.
  • 8. F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Boston, MA, USA; AND Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; AND Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.
  • 9. Neurocenter, Humanitas Clinical and Research Center - IRCCS, Rozzano (MI), Italy; AND CNR Institute of Neuroscience, Milano, Italy.

Description

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.

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