Impaired Synaptic Vesicle Release and Immaturity of Neuromuscular Junctions in Spinal Muscular Atrophy Mice

摘要: The motor neuron disease spinal muscular atrophy (SMA) causes profound muscle weakness that most often leads to early death. At autopsy, SMA is characterized by loss of neurons and atrophy, but the initial cellular events precipitate unit dysfunction remain poorly characterized. Here, we examined function corresponding structure neuromuscular junction (NMJ) synapses in a mouse model severe (hSMN2/delta7SMN/mSmn−/−). Surprisingly, NMJs remained innervated even late course; however they showed abnormal synaptic transmission. There was two-fold reduction amplitudes evoked endplate currents (EPCs), normal spontaneous miniature EPC (MEPC) amplitudes. These features combination indicate reduced quantal content. also demonstrated increased facilitation suggesting probability vesicle release. By electron microscopy, found decreased density vesicles likely contribute release probability. In addition presynaptic defects, there were postsynaptic abnormalities. MEPC decay time constants prolonged because slowed switch from fetal acetylcholine receptor (AChR) γ-subunit adult e-subunit. size AChR clusters small myofibers, which expressed an immature pattern myosin heavy chains. Together these results impaired at failed postnatal maturation units weakness.