Spinal Cord Injury Versus Sciatic Nerve Injury: Divergent Neuromuscular Pathologies and Neural Circuitry Remodeling

ABSTRACT Spinal cord injury (SCI) and sciatic nerve injury (SNI) represent distinct neurotrauma models with different pathological outcomes. Although both injuries result in severe motor and sensory dysfunction in the lower limbs, their divergent mechanisms of muscle atrophy and neural circuit remodeling remain poorly understood. This study systematically compared electrophysiological and morphological alterations at multiple time points post‐injury. At 4 weeks, SNI induced severe muscle atrophy and complete loss of compound muscle action potentials (CMAPs), whereas SCI caused mild atrophy and moderate CMAP amplitude reduction. Neuromuscular junctions were fully denervated within 1 week after SNI but remained intact in SCI. Neither SCI nor SNI altered motor neuron number/area, though SNI triggered transient NeuN downregulation in these neurons. Divergent neural circuit reorganization also occurred: SNI eliminated vGluT1⁺ Ia synapses from ventral horn motor neurons, while SCI promoted vGluT1⁺ Ia afferent sprouting alongside reduced GAD65⁺ inhibitory terminals. Additionally, glial responses differed markedly: SCI induced widespread spinal microgliosis/astrocytosis, whereas SNI caused localized ventral/dorsal horn gliosis near axotomized neurons. Nociceptive fiber plasticity also diverged: SCI upregulated CGRP⁺ dorsal horn terminals without affecting IB4⁺ fibers, while SNI abolished both CGRP⁺ and IB4⁺ terminals. These findings demonstrate fundamentally distinct pathological cascades in SCI versus SNI, providing mechanistic insights for developing tailored neurotrauma treatments.