Post-synaptic morphology of mouse neuromuscular junctions is linked to muscle fibre type
Post-synaptic morphology of mouse neuromuscular junctions is linked to muscle fibre type
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DOI：
10.1101/2020.04.04.025106
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发表时间：
2020-04
期刊：
影响因子：
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通讯作者：
Aleksandra M. Mech;Anna L. Brown;G. Schiavo;J. Sleigh
中科院分区：
文献类型：
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作者：
Aleksandra M. Mech;Anna L. Brown;G. Schiavo;J. Sleigh
神经肌肉接头（NMJ）是下运动神经元终末和肌纤维之间形成的高度特化的外周突触。突触后乙酰胆碱受体（AChR）在肌膜中以高密度存在，其与释放到NMJ的突触间隙中的乙酰胆碱结合，最终促进运动动作电位转化为肌肉收缩。NMJ作为突触形成、发育和功能的一般模型已被研究多年，并且已知是许多神经肌肉疾病中病理变化的早期部位。然而，关于不同肌肉中NMJ的多样性，肌纤维类型是否影响NMJ形态和生长以及这些参数与神经病理学的相关性的信息有限。在这里，这个关键的差距是使用一个强大的和标准化的半自动化的工作流程称为NMJ-形态，以量化的功能，突触前和突触后NMJ架构以公正的方式来解决。在未成熟（出生后，P7）和早期成年（P31-32）时间点，解剖并比较了野生型小鼠的5块全负荷肌肉。突触后AChR形态被认为是更可变的肌肉之间比运动神经元末梢和有更大的差异，在发展中的NMJ比在成熟的突触。突触后结构，而不是神经元形态或出生后突触生长，与纤维类型相关，在很大程度上独立于肌纤维直径。与以前的观察相反，这项研究表明，较小的NMJ倾向于神经支配具有较高比例的快缩纤维的肌肉，并且NMJ的生长速率在所有肌肉中并不保守。此外，健康的突触前和突触后NMJ形态参数收集五个解剖学和功能不同的小鼠肌肉，生成的参考数据，将是有用的神经肌肉疾病模型的未来评估。图形摘要
The neuromuscular junction (NMJ) is the highly specialised peripheral synapse formed between lower motor neuron terminals and muscle fibres. Post-synaptic acetylcholine receptors (AChRs), which are found in high density in the muscle membrane, bind to acetylcholine released into the synaptic cleft of the NMJ, ultimately facilitating the conversion of motor action potentials to muscle contractions. NMJs have been studied for many years as a general model for synapse formation, development and function, and are known to be early sites of pathological changes in many neuromuscular diseases. However, information is limited on the diversity of NMJs in different muscles, whether muscle fibre type impacts NMJ morphology and growth, and the relevance of these parameters to neuropathology. Here, this crucial gap was addressed using a robust and standardised semi-automated workflow called NMJ-morph to quantify features of pre- and post-synaptic NMJ architecture in an unbiased manner. Five wholemount muscles from wild-type mice were dissected and compared at immature (post-natal day, P7) and early adult (P31-32) timepoints. Post-synaptic AChR morphology was found to be more variable between muscles than that of the motor neuron terminal and there were greater differences in the developing NMJ than at the mature synapse. Post-synaptic architecture, but not neuronal morphology or post-natal synapse growth, correlates with fibre type and is largely independent of muscle fibre diameter. Counter to previous observations, this study indicates that smaller NMJs tend to innervate muscles with higher proportions of fast twitch fibres and that NMJ growth rate is not conserved across all muscles. Furthermore, healthy pre- and post-synaptic NMJ morphological parameters were collected for five anatomically and functionally distinct mouse muscles, generating reference data that will be useful for the future assessment of neuromuscular disease models. Graphical Abstract