Amyotrophic lateral sclerosis is a fatal disease resulting from motor neuron degeneration in the cortex and spinal cord. Cortical hyperexcitability is a hallmark feature of amyotrophic lateral sclerosis and is accompanied by decreased intracortical inhibition. Using electrophysiological patch-clamp recordings, we revealed parvalbumin interneurons to be hypoactive in the late pre-symptomatic SOD1*G93A mouse model of amyotrophic lateral sclerosis. We discovered that using adeno-associated virus-mediated delivery of chemogenetic technology targeted to increase the activity of the interneurons within layer 5 of the primary motor cortex, we were able to rescue intracortical inhibition and reduce pyramidal neuron hyperexcitability. Increasing the activity of interneurons in the layer 5 of the primary motor cortex was effective in delaying the onset of amyotrophic lateral sclerosis-associated motor deficits, slowing symptom progression, preserving neuronal populations, and increasing the lifespan of SOD1*G93A mice. Taken together, this study provides novel insights into the pathogenesis and treatment of amyotrophic lateral sclerosis.

中文翻译：

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皮层神经元介导的抑制作用可延迟肌萎缩性侧索硬化症的发作。

肌萎缩性侧索硬化症是由皮质和脊髓中的运动神经元变性导致的致命疾病。皮质过度兴奋是肌萎缩性侧索硬化的标志性特征，并伴有皮质内抑制的降低。使用电生理膜片钳记录，我们发现小白蛋白中间神经元在肌萎缩性侧索硬化症的症状前SOD1 * G93A小鼠晚期晚期模型中活性不足。我们发现，使用腺相关病毒介导的化学生成技术来增加初级运动皮层第5层内神经元的活性，我们能够挽救皮质内抑制并减少锥体神经元过度兴奋。增加初级运动皮层第5层中神经元的活性可有效延迟肌萎缩性侧索硬化相关运动功能障碍的发作，减慢症状进展，保留神经元种群并延长SOD1 * G93A小鼠的寿命。两者合计，这项研究提供了肌萎缩性侧索硬化症的发病机理和治疗的新见解。