# Disuse plasticity limits spinal cord injury recovery

## TL;DR

Early disuse after spinal cord injury harms long-term recovery by causing lasting changes in spinal circuits and receptors.

## Contribution

The study reveals how early disuse leads to maladaptive spinal plasticity that limits recovery after spinal cord injury.

## Key findings

- Early disuse in the acute phase of SCI reduces long-term locomotor recovery.
- Disuse increases chronic spinal circuit hyperexcitability and alters AMPA receptor composition.
- Unsupervised machine learning links synaptic changes to recovery deficits in SCI.

## Abstract

Use-dependent plasticity after spinal cord injury (SCI) enhances neuromotor function, however, the optimal timing to initiate rehabilitation remains controversial. To test impacts of early disuse, we established a rodent model of transient hindlimb suspension in acute phase SCI. Early disuse in the first 2-week after SCI undermined recovery on open-field locomotion, kinematics, and swim tests even after 6-week of normal gravity reloading. Early disuse produced chronic spinal circuit hyper-excitability in H-reflex and interlimb reflex tests. Quantitative synaptoneurosome analysis of lumboventral spinal cords revealed shifts in AMPA receptor (AMPAR) subunit GluA1 localization and serine 881 phosphorylation, reflecting enduring synaptic memories of early disuse stored in the spinal cord. Automated confocal analysis of motoneurons revealed persistent shifts toward GluA2-lacking, calcium-permeable AMPARs in disuse subjects. Unsupervised machine learning associated multidimensional synaptic changes with persistent recovery deficits in SCI. The results argue for early aggressive rehabilitation to prevent disuse plasticity that limits SCI recovery.

•Early disuse undermines long-term locomotor recovery after spinal cord injury•Early disuse induces chronic hyperexcitability of spinal reflexes after injury•Early disuse overdrives GluA2-lacking AMPA receptors in chronic spinal cord injury•Maladaptive spinal plasticity due to disuse hinders sustained recovery after injury

Early disuse undermines long-term locomotor recovery after spinal cord injury

Early disuse induces chronic hyperexcitability of spinal reflexes after injury

Early disuse overdrives GluA2-lacking AMPA receptors in chronic spinal cord injury

Maladaptive spinal plasticity due to disuse hinders sustained recovery after injury

Biological sciences; Neuroscience; Machine learning