Modulation of central synapse remodeling after remote peripheral injuries by the CCL2-CCR2 axis and microglia

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Microglia play a role in synaptic plasticity following central nervous system (CNS) injury.
• The mechanisms by which microglia modulate synaptic plasticity based on injury severity are not fully understood.

Purpose of the Study:

• To investigate the differential effects of microglia on spinal motor synaptic circuits after varying nerve injuries.
• To elucidate the mechanisms underlying microglia-mediated synapse removal or preservation.

Main Methods:

• Comparison of microglia activation and synaptic changes after nerve transection versus nerve crush injuries.
• Genetic deletion of CCL2 in microglia.
• Assessment of Ia axon and synapse dynamics.
• Analysis of motor neuron regeneration and associated factors.

Main Results:

• Nerve transection leads to permanent Ia synapse removal by microglia via C-C chemokine receptor type 2 signaling.
• Milder nerve crush injuries allow for Ia synapse and stretch reflex recovery.
• Prolonged microglia activation, linked to slower motor axon regeneration and sustained colony-stimulating factor type 1 expression, drives CCL2 induction and synapse elimination.
• Deleting CCL2 from microglia prevents synapse removal after nerve transection.
• Synapse preservation did not fully restore stretch-reflex function.

Conclusions:

• Microglia-mediated synapse removal is dependent on specific microglia phenotypes induced by nerve regeneration efficiency.
• The duration of microglia activation is a critical factor in determining synaptic plasticity outcomes after CNS injury.
• While microglia influence synapse dynamics, complete functional recovery of reflexes requires additional mechanisms beyond synapse preservation.