Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark.
Department of Computer Science, University of Copenhagen, Copenhagen N, Denmark.
Nat Commun. 2021 May 31;12(1):3251. doi: 10.1038/s41467-021-23224-7.
ALS is characterized by progressive inability to execute movements. Motor neurons innervating fast-twitch muscle-fibers preferentially degenerate. The reason for this differential vulnerability and its consequences on motor output is not known. Here, we uncover that fast motor neurons receive stronger inhibitory synaptic inputs than slow motor neurons, and disease progression in the SOD1 mouse model leads to specific loss of inhibitory synapses onto fast motor neurons. Inhibitory V1 interneurons show similar innervation pattern and loss of synapses. Moreover, from postnatal day 63, there is a loss of V1 interneurons in the SOD1 mouse. The V1 interneuron degeneration appears before motor neuron death and is paralleled by the development of a specific locomotor deficit affecting speed and limb coordination. This distinct ALS-induced locomotor deficit is phenocopied in wild-type mice but not in SOD1 mice after appearing of the locomotor phenotype when V1 spinal interneurons are silenced. Our study identifies a potential source of non-autonomous motor neuronal vulnerability in ALS and links ALS-induced changes in locomotor phenotype to inhibitory V1-interneurons.
肌萎缩侧索硬化症（ALS）的特征是进行性运动能力丧失。快速收缩肌纤维支配的运动神经元优先退化。这种差异易损性的原因及其对运动输出的影响尚不清楚。在这里，我们发现快速运动神经元接收的抑制性突触输入比慢速运动神经元更强，SOD1 小鼠模型中的疾病进展导致快速运动神经元上特定的抑制性突触丧失。抑制性 V1 中间神经元表现出相似的支配模式和突触丧失。此外，从出生后第 63 天开始，SOD1 小鼠中 V1 中间神经元发生丢失。V1 中间神经元的退化发生在运动神经元死亡之前，并且与特定的运动缺陷的发展平行，该缺陷影响速度和肢体协调性。在出现运动表型后，当 V1 脊髓中间神经元被沉默时，这种独特的 ALS 诱导的运动缺陷在野生型小鼠中被复制，但在 SOD1 小鼠中未被复制。我们的研究确定了 ALS 中非自主运动神经元易损性的一个潜在来源，并将 ALS 诱导的运动表型变化与抑制性 V1 中间神经元联系起来。
