Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia

Area of Science:

• Neuroscience
• Cell Biology
• Developmental Biology

Background:

• Neuronal circuit assembly relies on balancing synapse formation and elimination.
• Microglia are known to eliminate supernumerary synapses, a process crucial for neural development.
• Key molecules like TREM2, C1q, and C3 are implicated, but neuronal signals for synapse elimination remain unclear.

Purpose of the Study:

• To identify neuronal molecular components that signal synapses for elimination by microglia.
• To elucidate the role of exposed phosphatidylserine (PS) as a potential "eat-me" signal in microglial-mediated synaptic pruning.

Main Methods:

• Utilized hippocampal neuron and microglia co-cultures to study synapse elimination.
• Employed Annexin V to block exposed PS and observed effects on synapse elimination.
• Investigated microglial loss of TREM2 function in co-cultures.
• Examined PS exposure and microglial engulfment in vivo in hippocampal and retinogeniculate synapses.
• Analyzed PS exposure and microglial engulfment in C1q-deficient mice.

Main Results:

• Exposed phosphatidylserine (PS) was identified as a neuronal "eat-me" signal mediating microglial pruning.
• Blocking PS accessibility or TREM2 function partially prevented synapse elimination in co-cultures.
• Developmentally regulated PS exposure and microglial engulfment were observed in vivo.
• C1q-deficient mice showed increased presynaptic PS exposure and reduced microglial engulfment, alongside impaired retinogeniculate refinement.

Conclusions:

• Developmentally regulated neuronal PS exposure is a novel mechanism guiding microglial-mediated synapse pruning.
• This PS-mediated pathway provides mechanistic insight into synaptic refinement across developing brain structures.
• Identifies a conserved mechanism for synaptic pruning involving neuronal "eat-me" signals.