Modulation of central synapse remodeling after remote peripheral injuries by the CCL2-CCR2 axis and microglia
Travis M. Rotterman,
Zoë Haley-Johnson,
Tana S. Pottorf,
Tavishi Chopra,
Ethan Chang,
Shannon Zhang,
William M. McCallum,
Sarah Fisher,
Haley Franklin,
Myriam Alvarez,
Timothy C. Cope,
Francisco J. Alvarez
Affiliations
Travis M. Rotterman
Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30318, USA
Zoë Haley-Johnson
Department of Cell Biology, Emory University, Atlanta, GA 30322, USA
Tana S. Pottorf
Department of Cell Biology, Emory University, Atlanta, GA 30322, USA
Tavishi Chopra
Department of Cell Biology, Emory University, Atlanta, GA 30322, USA
Ethan Chang
School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30318, USA
Shannon Zhang
Department of Cell Biology, Emory University, Atlanta, GA 30322, USA
William M. McCallum
Department of Cell Biology, Emory University, Atlanta, GA 30322, USA
Sarah Fisher
Department of Cell Biology, Emory University, Atlanta, GA 30322, USA
Haley Franklin
Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; The Alabama College of Osteopathic Medicine, Dothan, AL 36301, USA
Myriam Alvarez
Department of Cell Biology, Emory University, Atlanta, GA 30322, USA
Timothy C. Cope
School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30318, USA; W.H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA 30332, USA
Francisco J. Alvarez
Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Corresponding author
Summary: Microglia-mediated synaptic plasticity after CNS injury varies depending on injury severity, but the mechanisms that adjust synaptic plasticity according to injury differences are largely unknown. This study investigates differential actions of microglia on essential spinal motor synaptic circuits following different kinds of nerve injuries. Following nerve transection, microglia and C-C chemokine receptor type 2 signaling permanently remove Ia axons and synapses from the ventral horn, degrading proprioceptive feedback during motor actions and abolishing stretch reflexes. However, Ia synapses and reflexes recover after milder injuries (nerve crush). These different outcomes are related to the length of microglia activation, being longer after nerve cuts, with slower motor-axon regeneration and extended expression of colony-stimulating factor type 1 in injured motoneurons. Prolonged microglia activation induces CCL2 expression, and Ia synapses recover after ccl2 is deleted from microglia. Thus, microglia Ia synapse removal requires the induction of specific microglia phenotypes modulated by nerve regeneration efficiencies. However, synapse preservation was not sufficient to restore the stretch-reflex function.
