How do we get from hyperexcitability to excitotoxicity in amyotrophic lateral sclerosis?

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 road map 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.