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1.
J Neurosci ; 41(38): 8088-8101, 2021 09 22.
Article in English | MEDLINE | ID: mdl-34380764

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease with progressive motor neuron death, where patients usually die within 5 years of diagnosis. Previously, we showed that the C-boutons, which are large cholinergic synapses to motor neurons that modulate motor neuron activity, are necessary for behavioral compensation in mSOD1G93A mice, a mouse model for ALS. We reasoned that, since the C-boutons likely increase the excitability of surviving motor neurons to compensate for motor neuron loss during ALS disease progression, then amplitude modulation through the C-boutons likely increases motor neuron stress and worsens disease progression. By comparing male and female mSOD1G93A mice to mSOD1G93A mice with genetically silenced C-boutons [mSOD1G93A ; Dbx1::cre; ChATfl/fl (mSOD1G93A/Coff )], we show that the C-boutons do not influence the humane end point of mSOD1G93A mice; however, our histologic analysis shows that C-bouton silencing significantly improves fast-twitch muscle innervation over time. Using immunohistology, we also show that the C-boutons are active in a task-dependent manner, and that symptomatic mSOD1G93A mice show significantly higher C-bouton activity than wild-type mice during low-intensity walking. Last, by using behavioral analysis, we provide evidence that C-bouton silencing in combination with swimming is beneficial for the behavioral capabilities of mSOD1G93A mice. Our observations suggest that manipulating the C-boutons in combination with a modulatory-targeted training program may therefore be beneficial for ALS patients and could result in improved mobility and quality of life.SIGNIFICANCE STATEMENT Despite decades of research on amyotrophic lateral sclerosis (ALS), there have been little improvements in treatments and therapies. We sought to better understand how the activation of C-boutons, which are large cholinergic modulatory synapses on motor neurons, change and affect the disease as it progresses. When these C-boutons are genetically silenced and exercises designed to otherwise activate the C-boutons are frequently performed in ALS model mice, the mice perform better than their untreated counterparts over time. C-bouton-targeted therapies could therefore be beneficial for ALS patients and could result in improved mobility and quality of life.


Subject(s)
Amyotrophic Lateral Sclerosis/pathology , Cholinergic Neurons/pathology , Motor Neurons/pathology , Synapses/pathology , Amyotrophic Lateral Sclerosis/genetics , Animals , Disease Models, Animal , Disease Progression , Female , Male , Mice , Mice, Transgenic , Superoxide Dismutase-1/genetics
2.
Behav Brain Res ; 369: 111914, 2019 09 02.
Article in English | MEDLINE | ID: mdl-31022419

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.


Subject(s)
Amyotrophic Lateral Sclerosis/physiopathology , Cholinergic Neurons/physiology , Interneurons/physiology , Motor Activity/physiology , Motor Neurons/physiology , Acetylcholine/metabolism , Amyotrophic Lateral Sclerosis/pathology , Animals , Cholinergic Neurons/pathology , Disease Models, Animal , Disease Progression , Female , Interneurons/pathology , Male , Mice, Inbred C57BL , Mice, Transgenic , Motor Neurons/pathology , Muscle, Skeletal/innervation , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Neuromuscular Junction/pathology , Neuromuscular Junction/physiology , Receptor, Muscarinic M2/metabolism , Superoxide Dismutase-1/genetics , Superoxide Dismutase-1/metabolism
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