Amyotrophic lateral sclerosis is a devastating neurodegenerative disease that, at present, has no effective cure. Evidence of increased circulating glutamate and hyperexcitability of the motor cortex in patients with amyotrophic lateral sclerosis have provided an empirical support base for the ‘dying forward’ excitotoxicity hypothesis. The hypothesis postulates that increased activation of upper motor neurons spreads pathology to lower motor neurons in the spinal cord in the form of excessive glutamate release, which triggers excitotoxic processes. Many clinical trials have focused on therapies that target excitotoxicity via dampening neuronal activation, but not all are effective. As such, there is a growing tension between the rising tide of evidence for the dying forward excitotoxicity hypothesis and the failure of therapies that target neuronal activation. One possible solution to these contradictory outcomes is that our interpretation of the current evidence requires revision in the context of appreciating the complexity of the nervous system and the limitations of the neurobiological assays we use to study it. In this review we provide an evaluation of evidence relevant to the dying forward excitotoxicity hypothesis and by doing so, identify key gaps in our knowledge that need to be addressed. We hope to provide a roadmap from hyperexcitability to excitotoxicity so that we can better develop therapies for patients suffering from amyotrophic lateral sclerosis. We conclude that studies of upper motor neuron activity and their synaptic output will play a decisive role in the future of amyotrophic lateral sclerosis therapy.

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肌萎缩侧索硬化症患者如何从过度兴奋转变为兴奋性毒性？

肌萎缩侧索硬化症是一种毁灭性的神经退行性疾病，目前尚无有效的治疗方法。肌萎缩侧索硬化症患者循环谷氨酸增加和运动皮层过度兴奋的证据为“垂死前进”兴奋性毒性假说提供了经验支持基础。该假设假设，上运动神经元的激活增加会以过量谷氨酸释放的形式将病理传播到脊髓中的下运动神经元，从而引发兴奋性毒性过程。许多临床试验都集中在通过抑制神经元激活来靶向兴奋性毒性的疗法，但并非所有试验都有效。因此，越来越多的证据表明兴奋性毒性假说即将消失，而针对神经元激活的疗法却失败了，两者之间的关系日益紧张。对于这些矛盾结果的一种可能的解决方案是，我们对当前证据的解释需要在认识到神经系统的复杂性和我们用来研究它的神经生物学测定的局限性的背景下进行修订。在这篇综述中，我们对与垂死前向兴奋性毒性假说相关的证据进行了评估，并通过这样做，确定了我们知识中需要解决的关键差距。我们希望提供从过度兴奋到兴奋毒性的路线图，以便我们能够更好地为肌萎缩侧索硬化症患者开发治疗方法。我们的结论是，对上运动神经元活动及其突触输出的研究将在肌萎缩侧索硬化症治疗的未来中发挥决定性作用。