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首页> 外文期刊>Molecular and Cellular Biology >Aberrant Morphology and Residual Transmitter Release at the Munc13-Deficient Mouse Neuromuscular Synapse
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Aberrant Morphology and Residual Transmitter Release at the Munc13-Deficient Mouse Neuromuscular Synapse

机译：Munc13缺陷小鼠神经肌肉突触的异常形态和残留的递质释放。

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In cultured hippocampal neurons, synaptogenesis is largely independent of synaptic transmission, while several accounts in the literature indicate that synaptogenesis at cholinergic neuromuscular junctions in mammals appears to partially depend on synaptic activity. To systematically examine the role of synaptic activity in synaptogenesis at the neuromuscular junction, we investigated neuromuscular synaptogenesis and neurotransmitter release of mice lacking all synaptic vesicle priming proteins of the Munc13 family. Munc13-deficient mice are completely paralyzed at birth and die immediately, but form specialized neuromuscular endplates that display typical synaptic features. However, the distribution, number, size, and shape of these synapses, as well as the number of motor neurons they originate from and the maturation state of muscle cells, are profoundly altered. Surprisingly, Munc13-deficient synapses exhibit significantly increased spontaneous quantal acetylcholine release, although fewer fusion-competent synaptic vesicles are present and nerve stimulation-evoked secretion is hardly elicitable and strongly reduced in magnitude. We conclude that the residual transmitter release in Munc13-deficient mice is not sufficient to sustain normal synaptogenesis at the neuromuscular junction, essentially causing morphological aberrations that are also seen upon total blockade of neuromuscular transmission in other genetic models. Our data confirm the importance of Munc13 proteins in synaptic vesicle priming at the neuromuscular junction but indicate also that priming at this synapse may differ from priming at glutamatergic and γ-aminobutyric acid-ergic synapses and is partly Munc13 independent. Thus, non-Munc13 priming proteins exist at this synapse or vesicle priming occurs in part spontaneously: i.e., without dedicated priming proteins in the release machinery.
机译：在培养的海马神经元中，突触的发生在很大程度上与突触的传递无关，而文献中的一些报道表明在哺乳动物的胆碱能神经肌肉接头处的突触发生似乎部分地取决于突触的活性。为了系统地检查突触活性在神经肌肉连接处突触形成中的作用，我们调查了缺少Munc13家族所有突触囊泡启动蛋白的小鼠的神经肌肉突触形成和神经递质释放。缺乏Munc13的小鼠在出生时会完全瘫痪并立即死亡，但会形成专门的神经肌肉终板，表现出典型的突触特征。但是，这些突触的分布，数量，大小和形状以及它们起源的运动神经元的数量和肌肉细胞的成熟状态都发生了深刻的变化。出乎意料的是，尽管存在较少的具有融合能力的突触囊泡，并且几乎不能引起神经刺激诱发的分泌并且其幅度大大降低，但缺乏Munc13的突触表现出明显的自发定量乙酰胆碱释放。我们得出的结论是，在Munc13缺陷型小鼠中，残留的递质释放不足以维持神经肌肉接头处的正常突触发生，这实质上会导致形态异常，在其他遗传模型中完全阻断神经肌肉传输也可以看到这种异常。我们的数据证实了Munc13蛋白在神经肌肉交界处的突触小泡引发中的重要性，但也表明在该突触处的引发可能不同于在谷氨酸能和γ-氨基丁酸-能突触处的引发，并且部分地独立于Munc13。因此，在该突触处存在非Munc13启动蛋白，或者囊泡启动部分自发地发生：即，在释放机制中没有专用的启动蛋白。

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