Hypoexcitability precedes denervation in the large fast-contracting motor units in two unrelated mouse models of ALS

• Published in: eLife Vol. 7
• Main Authors: Martínez-Silva, María de Lourdes, Imhoff-Manuel, Rebecca D, Sharma, Aarti, Heckman, C J, Shneider, Neil A, Roselli, Francesco, Zytnicki, Daniel, Manuel, Marin
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 27-03-2018; eLife Sciences Publication; eLife Sciences Publications, Ltd
• Subjects: Action Potentials; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - pathology; Amyotrophic Lateral Sclerosis - physiopathology; Animal models; Animals; Cognitive science; Contractility; Cortical Excitability; Degeneration; Denervation; Disease Models, Animal; Electrical properties; electrophysiology; firing properties; in vivo intracellular recordings; Medical research; Medicine; Mice; motoneuron; motor neuron; Motor neurons; Motor Neurons - pathology; Motor units; Neuromuscular junctions; Neuroscience; Physiology; United States > US; Chicago Illinois; mouse; electrophysiology; motor neuron; neuroscience; motoneuron; firing properties; in vivo intracellular recordings
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.30955

Hyperexcitability has been suggested to contribute to motoneuron degeneration in amyotrophic lateral sclerosis (ALS). If this is so, and given that the physiological type of a motor unit determines the relative susceptibility of its motoneuron in ALS, then one would expect the most vulnerable motoneurons to display the strongest hyperexcitability prior to their degeneration, whereas the less vulnerable should display a moderate hyperexcitability, if any. We tested this hypothesis in vivo in two unrelated ALS mouse models by correlating the electrical properties of motoneurons with their physiological types, identified based on their motor unit contractile properties. We found that, far from being hyperexcitable, the most vulnerable motoneurons become unable to fire repetitively despite the fact that their neuromuscular junctions were still functional. Disease markers confirm that this loss of function is an early sign of degeneration. Our results indicate that intrinsic hyperexcitability is unlikely to be the cause of motoneuron degeneration.