Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis
Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis
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DOI：
10.7554/elife.04046
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发表时间：
2014-10-14
期刊：
影响因子：
7.7
通讯作者：
Zytnicki, Daniel
中科院分区：
文献类型：
--
作者：
Leroy, Felix;d'Incamps, Boris Lamotte;Zytnicki, Daniel
在肌萎缩侧索硬化症（ALS）中，支配快速收缩肌纤维的大型运动神经元（F-型运动神经元）在成年后变得脆弱和退化。相反，支配缓慢收缩纤维的小运动神经元（S型运动神经元）具有抵抗力，不会退化。出生后早期发育过程中的F-型运动神经元的内在过度兴奋性一直被认为是导致成年后神经退行性变的原因。在这里，我们进行了一个关键的测试，这一假设通过记录从确定的F-和S-型运动神经元的超氧化物歧化酶-1突变体G93 A（mSOD 1），小鼠模型ALS在新生儿年龄时，观察到早期的病理生理变化。与标准假设相反，突变小鼠的F-型运动神经元的兴奋性没有变化。令人惊讶的是，mSDO 1小鼠的S型运动神经元确实表现出固有的过度兴奋性（较低的基强度，超极化尖峰阈值）。由于S型运动神经元在ALS中具有抵抗性，我们得出结论，早期内在的过度兴奋并不导致运动神经元变性。
In amyotrophic lateral sclerosis (ALS) the large motoneurons that innervate the fast-contracting muscle fibers (F-type motoneurons) are vulnerable and degenerate in adulthood. In contrast, the small motoneurons that innervate the slow-contracting fibers (S-type motoneurons) are resistant and do not degenerate. Intrinsic hyperexcitability of F-type motoneurons during early postnatal development has long been hypothesized to contribute to neural degeneration in the adult. Here, we performed a critical test of this hypothesis by recording from identified F- and S-type motoneurons in the superoxide dismutase-1 mutant G93A (mSOD1), a mouse model of ALS at a neonatal age when early pathophysiological changes are observed. Contrary to the standard hypothesis, excitability of F-type motoneurons was unchanged in the mutant mice. Surprisingly, the S-type motoneurons of mSDO1 mice did display intrinsic hyperexcitability (lower rheobase, hyperpolarized spiking threshold). As S-type motoneurons are resistant in ALS, we conclude that early intrinsic hyperexcitability does not contribute to motoneuron degeneration.