Impaired synaptic vesicle release and immaturity of neuromuscular junctions in spinal muscular atrophy mice.
Impaired synaptic vesicle release and immaturity of neuromuscular junctions in spinal muscular atrophy mice.
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DOI：
10.1523/jneurosci.4434-08.2009
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发表时间：
2009-01-21
期刊：
影响因子：
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通讯作者：
Sumner CJ
中科院分区：
文献类型：
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作者：
Kong L;Wang X;Choe DW;Polley M;Burnett BG;Bosch-Marcé M;Griffin JW;Rich MM;Sumner CJ
运动神经元病脊髓性肌萎缩症 (SMA) 会导致严重的肌肉无力，最常导致过早死亡。在尸检中，SMA 的特征是运动神经元丧失和肌肉萎缩，但导致运动单位功能障碍和丧失的初始细胞事件仍然很少被表征。在这里，我们检查了严重 SMA 小鼠模型 (hSMN2/delta7SMN/mSmn-/-) 中神经肌肉接头 (NMJ) 突触的功能和相应结构。令人惊讶的是，即使在病程晚期，大多数 SMA NMJ 仍然受到神经支配。然而，它们表现出异常的突触传递。诱发终板电流 (EPC) 的振幅减少两倍，但自发微型 EPC (MEPC) 振幅正常。这些特征结合起来表明量子含量减少。 SMA NMJ 还表现出促进作用增加，表明囊泡释放的可能性降低。通过电子显微镜，我们发现突触小泡的密度降低，这可能导致释放概率降低。除了突触前缺陷外，还存在突触后异常。由于从胎儿乙酰胆碱受体 (AChR) γ 亚基到成人 ε 亚基的转换减慢，EPC 和 MEPC 衰减时间常数延长。 AChR 簇和小肌纤维的尺寸也减小，这表示肌球蛋白重链的不成熟模式。这些结果共同表明，严重 SMA 中 NMJ 突触小泡释放受损可能导致出生后运动单位成熟失败和肌肉无力。
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 motor neurons and muscle atrophy, but the initial cellular events that precipitate motor unit dysfunction and loss remain poorly characterized. Here, we examined the function and corresponding structure of neuromuscular junction (NMJ) synapses in a mouse model of severe SMA (hSMN2/delta7SMN/mSmn-/-). Surprisingly, most SMA NMJs remained innervated even late in the disease course; however they showed abnormal synaptic transmission. There was a two-fold reduction in the amplitudes of the evoked endplate currents (EPCs), but normal spontaneous miniature EPC (MEPC) amplitudes. These features in combination indicate reduced quantal content. SMA NMJs also demonstrated increased facilitation suggesting a reduced probability of vesicle release. By electron microscopy, we found a decreased density of synaptic vesicles that is likely to contribute to the reduced release probability. In addition to presynaptic defects, there were postsynaptic abnormalities. EPC and MEPC decay time constants were prolonged due to a slowed switch from the fetal acetylcholine receptor (AChR) γ-subunit to the adult ∈ subunit. There was also reduced size of AChR clusters and small myofibers, which expressed an immature pattern of myosin heavy chains. Together these results indicate that impaired synaptic vesicle release at NMJs in severe SMA is likely to contribute to failed post-natal maturation of motor units and muscle weakness.