Aberrant morphology and residual transmitter release at the Munc13-deficient mouse neuromuscular synapse
Aberrant morphology and residual transmitter release at the Munc13-deficient mouse neuromuscular synapse
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DOI：
10.1128/mcb.25.14.5973-5984.2005
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发表时间：
2005-07-01
影响因子：
5.3
通讯作者：
Brose, N
中科院分区：
文献类型：
--
作者：
Varoqueaux, F;Sons, MS;Brose, N
在培养的海马神经元中，突触发生在很大程度上独立于突触传递，而一些文献表明，哺乳动物胆碱能神经肌肉连接处的突触发生似乎部分依赖于突触活动。为了系统地研究突触活动在神经肌肉连接处突触发生中的作用，我们研究了缺乏Munc[3]家族所有突触囊泡启动蛋白的小鼠的神经肌肉突触发生和神经递质释放。缺乏munc13的小鼠在出生时完全瘫痪并立即死亡，但形成特殊的神经肌肉终板，显示典型的突触特征。然而，这些突触的分布、数量、大小和形状，以及它们产生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改变。令人惊讶的是，munc13缺陷突触表现出明显增加的自发量子乙酰胆碱释放，尽管存在较少的融合能力突触囊泡，神经刺激引起的分泌难以诱导，且强度大大降低。我们得出结论，munc13缺陷小鼠的剩余递质释放不足以维持神经肌肉连接处的正常突触发生，本质上导致形态畸变，这种畸变在其他遗传模型中也可以在完全阻断神经肌肉传递时看到。我们的数据证实了Munc13蛋白在神经肌肉连接处突触囊泡启动中的重要性，但也表明该突触的启动可能不同于谷氨酸能突触和γ -氨基丁酸能突触的启动，并且部分独立于Munc13。因此，非munc13启动蛋白存在于该突触或囊泡启动部分自发发生：即在释放机制中没有专用的启动蛋白。
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 Munc][3 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 gamma-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.