1. Cholinergic modulation of motor neurons through the C-boutons are necessary for the locomotor compensation for severe motor neuron loss during amyotrophic lateral sclerosis disease progression
- Author
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Lauren M. Landoni, Turgay Akay, Jacob R. Myles, William Paganini Mayer, and Tyler L. Wells
- Subjects
Male ,Neuromuscular Junction ,Mice, Transgenic ,Motor Activity ,03 medical and health sciences ,Behavioral Neuroscience ,Superoxide Dismutase-1 ,0302 clinical medicine ,Interneurons ,Animals ,Medicine ,Amyotrophic lateral sclerosis ,Muscle, Skeletal ,030304 developmental biology ,Motor Neurons ,Denervation ,Receptor, Muscarinic M2 ,0303 health sciences ,Muscle Denervation ,business.industry ,Amyotrophic Lateral Sclerosis ,Muscle weakness ,Motor neuron ,medicine.disease ,Acetylcholine ,Cholinergic Neurons ,Mice, Inbred C57BL ,Motor unit ,Disease Models, Animal ,Electrophysiology ,medicine.anatomical_structure ,nervous system ,Disease Progression ,Cholinergic ,Female ,medicine.symptom ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by progressive motor neuron (MN) death that leads to muscle weakness, paralysis, and eventually death. When symptoms become clinically evident, patients and ALS model animals (mSod1G93A mice) have already lost a large portion of motor units, suggesting the existence of a compensatory mechanism that allows for reactively normal movement despite denervation. Furthermore, it has been shown that specialized cholinergic synapses, the C-boutons, regulate activity strength of motor output in a task dependent manner. We hypothesized that the cholinergic modulation of motor neurons through C-boutons increases motor neuron excitability, and that this C-bouton associated activity increase in surviving motor neurons could compensate for motor unit loss during ALS disease progression. We first provide a thorough analysis of the muscle denervation and behavioral changes in the mSod1G93A mice using immunohistology, electrophysiology, and quantitative analysis of locomotor behavior. Then, in support of our hypothesis, we show that task dependent modulation of hindlimb muscle activation that relies on C-bouton activation diminishes as the disease progresses. Furthermore, the capability of mSod1G93A mice to walk at higher speeds on a treadmill decreases significantly at younger ages when C-boutons are silenced. Our observations that C-bouton modulation of motor neurons is involved in compensation during ALS disease progression can have significant therapeutic implications for sustaining mobility and preserving the quality of life in human ALS patients.
- Published
- 2019
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