Alteration of the neuron-glial GABAergic cross-talk in the sciatic nerve of dystrophic mdx mice

Duchenne muscular dystrophy (DMD) is a lethal X-linked muscular disease characterized by the lack of dystrophin, a cytoskeletal protein expressed in muscles and other cell types. Progressive muscle degeneration and impairment of neuromuscular junction stability are main features of the disease, albeit nothing is known on growth, integrity, and functional properties of peripheral nerves. These processes might be regulated by bidirectional signals that myelinating and non-myelinating Schwann cells (SCs) establish with both motor and sensory neuron axons. A re-known regulator of SC-neuron cross-talk is the neurotransmitter GABA. Therefore, the aim of the research was to investigate whether DMD would affect motor and sensory neuron physiology and their morpho-functional relationship with SCs. The studies, performed on the sciatic nerve of wild type and dystrophic mdx mice, analyzed the expression and localization of proteins fundamental for myelin sheath integrity and SC-axon signaling. Real time RT-PCR demonstrated a significant reduction in mRNA levels of myelin proteins (e.g. MBP, P0, PMP22, MAG), and of inotropic GABA A (a4, b3, d) and metabotropic GABA B -1b receptor subunits in mdx mice compared to controls. Reduction in protein levels was confirmed by Western immunoblot (e.g MBP, GABAβ3, GABAδ, GABABR1), and corresponded to a decrease in the mean immunofluorescence intensity following confocal microscope analysis. Further preliminary electrophysiological analyses identified a significant reduction in sensory Abeta fiber excitability. Altogether, our findings support the hypothesis of significant alterations of neuron-SC cross-talk in peripheral nerves of mdx mice, an intriguing factor that should be considered for the development of new DMD therapeutic strategies.