ABERRANT SPINAL CORD ORGANIZATION AND GLIAL REMODELING IN MUSCULAR DYSTROPHIES

Duchenne muscular dystrophy (DMD), caused by dystrophin gene mutations, leads to progressive muscle degeneration and neurological comorbidities affecting brain and spinal cord isoforms. Despite its critical role in motor execution, spinal cord pathology remains underexplored. Recent human studies confirm dystrophin expression in anterior horn motor neurons (MNs), with its absence linked to GABAergic synapse instability, pyramidal degeneration resembling ALS, and motor deficits independent of muscle pathology. We characterized spinal cord cellular and molecular alterations in two DMD mouse models—mild B10.mdx (early degeneration-regeneration cycles) and severe D2.mdx (rapid fibrosis with diaphragm calcification)—correlating changes with disease progression and motor impairment.
Behavioral testing (Rotarod) revealed significant coordination and proprioception deficits in dystrophic mice versus wild-type controls, evidenced by reduced latency to fall. Immunohistochemical analyses of ventral horns demonstrated increased parvalbumin-positive inhibitory interneuron input onto alpha-MNs (ChAT+/NeuN+), with elevated VGAT puncta density on MNs innervating glycolytic degenerating fibers (reduced size and number). Enhanced glial morphological complexity, increased microglial (Iba1+) synaptic contacts, and prominent astrocyte activation were observed, particularly in aged D2.mdx mice, indicating sustained inflammatory and neuroprotective responses.
These findings reveal DMD-induced spinal cord remodeling characterized by exaggerated inhibitory signaling and gliosis, contributing to motor dysfunction beyond primary muscle pathology. This work extends our understanding of DMD pathology to encompass motor output pathways, highlighting spinal cord circuits as potential therapeutic targets for improving motor function in dystrophinopathies.