EFFECTS OF DYSTROPHIN LOSS AND DISEASE PROGRESSION ON GABAERGIC SYNAPTIC MARKERS IN THE SPINAL CORD OF <EM>MDX</EM> MICE, A MODEL OF DUCHENNE MUSCOLAR DYSTROPHY

Duchenne muscular dystrophy (DMD), caused by loss of dystrophin (Dp427), features progressive skeletal muscle degeneration but also affects multiple non-muscular tissues, including central (CNS) and peripheral nervous systems. This reflects the expression of Dp427, shorter isoforms, and dystrophin-associated glycoprotein complex (DGC) components in neuronal and glial cells. In neural tissues, the dystrophin-DGC complex organizes membrane domains, stabilizing receptors, ion channels, and signaling molecules. Notably, Dp427-DGC is enriched at postsynaptic inhibitory synapses in specific brain regions, where it modulates ionotropic GABA-A receptor clustering and network excitability. To date, the impact of dystrophin loss on the spinal cord, critical for sensorimotor integration, remains understudied. We investigated the lumbar spinal cord of dystrophic mdx mice versus wild-type at 6-7 weeks and 1 year, corresponding to early and advanced disease stages. Protein levels of key DGC components (α- and β-dystroglycan, dystrobrevin) and GABAergic markers (GABA-Aβ3, GABA-BR1, GAD65/67) were analyzed. GABA-BR1 and the presynaptic GABA-synthesizing enzyme GAD65 were significantly reduced in young mdx mice; GAD65 reduction persisted at 1 year, whereas GABA-BR1 levels became too low to quantify, pointing to impaired metabotropic inhibitory signaling within spinal sensorimotor circuits, worsening along disease progression. GABA-Aβ3 was unchanged between genotypes but declined with age in both. Among DGC components, β-dystroglycan was overexpressed in young mdx spinal cord but markedly reduced at 1 year, indicating DGC alterations. Finally, choline acetyltransferase immunohistochemistry revealed reduced motor neuron number and increased soma area. Altogether, these data support a previously underappreciated contribution of spinal cord dysfunction to sensorimotor alterations in DMD.