# Pharmacological Microglial Inhibition Remodels the Scar Microenvironment to Support Reticulospinal Circuit Reconstruction After Spinal Cord Injury

## TL;DR

This study shows that inhibiting microglia with a drug can change the spinal cord injury environment to allow nerve regeneration and restore motor function.

## Contribution

The study introduces pharmacological microglial inhibition as a novel strategy to promote spinal cord repair through scar remodeling.

## Key findings

- Pharmacological microglial inhibition reduces inhibitory extracellular matrix deposition after spinal cord injury.
- Reticulospinal tract regeneration and functional synapse reconstruction lead to motor recovery in complete spinal cord injury.
- Microglial transition to a homeostatic phenotype supports a permissive environment for axonal regrowth.

## Abstract

Due to an inhibitory scar microenvironment that prevents neural circuit reconstruction, spinal cord injury (SCI) often leads to persistent neurological dysfunction. Although neonatal murine models demonstrate that microglial inhibition enables scar remodeling to support neuroregeneration and functional recovery, effective pharmacological suppression of microglial activation in adult SCI remain elusive. Here, this work demonstrates that early β2‐adrenergic receptor agonist treatment drives microglial transition to a homeostatic phenotype within the post‐SCI scar. This intervention reduces inhibitory extracellular matrix deposition and transforms the inhibitory microenvironments into permissive substrates for axonal regrowth. Anatomical analyses reveal regeneration of the reticulospinal tract, which establishes synaptic connectivity with thoracolumbar circuits to mediate motor recovery in a complete SCI. These findings elucidate the therapeutic potential and neural circuit mechanisms underlying pharmacological microglial modulation for SCI repair, establishing a glial‐neural circuit reparative paradigm.

This study establishes pharmacological microglial inhibition as a therapeutic strategy, demonstrating its capacity to remodel the lesion microenvironment through significant reduction of extracellular matrix deposition. This permissive environmental transformation facilitates robust regeneration of the reticulospinal tract, and reconstructs functional synapses with local spinal circuits, and ultimately restores motor function.