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Escape from homeostasis: spinal microcircuits and progression of amyotrophic lateral sclerosis.

Brownstone, RM; Lancelin, C; (2018) Escape from homeostasis: spinal microcircuits and progression of amyotrophic lateral sclerosis. J Neurophysiol , 119 (5) pp. 1782-1794. 10.1152/jn.00331.2017. Green open access

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Abstract

In amyotrophic lateral sclerosis (ALS), loss of motoneuron function leads to weakness and, ultimately, respiratory failure and death. Regardless of the initial pathogenic factors, motoneuron loss follows a specific pattern: the largest α-motoneurons die before smaller α-motoneurons, and γ-motoneurons are spared. In this article, we examine how homeostatic responses to this orderly progression could lead to local microcircuit dysfunction that in turn propagates motoneuron dysfunction and death. We first review motoneuron diversity and the principle of α-γ coactivation and then discuss two specific spinal motoneuron microcircuits: those involving proprioceptive afferents and those involving Renshaw cells. Next, we propose that the overall homeostatic response of the nervous system is aimed at maintaining force output. Thus motoneuron degeneration would lead to an increase in inputs to motoneurons, and, because of the pattern of neuronal degeneration, would result in an imbalance in local microcircuit activity that would overwhelm initial homeostatic responses. We suggest that this activity would ultimately lead to excitotoxicity of motoneurons, which would hasten the progression of disease. Finally, we propose that should this be the case, new therapies targeted toward microcircuit dysfunction could slow the course of ALS.

Type: Article
Title: Escape from homeostasis: spinal microcircuits and progression of amyotrophic lateral sclerosis.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1152/jn.00331.2017
Publisher version: https://doi.org/10.1152/jn.00331.2017
Language: English
Additional information: Copyright © 2018 the American Physiological Society Licensed under Creative Commons Attribution CC-BY 4.0: © the American Physiological Society.
Keywords: Renshaw cells, excitotoxicity, muscle spindles, proprioceptive afferents, α-motoneurons, γ-motoneurons
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10048336
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