C-Boutons and Their Influence on Amyotrophic Lateral Sclerosis Disease Progression

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 <i>mSOD1^G93A</i> 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 <i>mSOD1^G93A</i> mice to <i>mSOD1^G93A</i> mice with genetically silenced C-boutons [<i>mSOD1^G93A</i>; <i>Dbx1::cre</i>; <i>ChAT^fl/fl</i> (<i>mSOD1^G93A/C^off</i>)], we show that the C-boutons do not influence the humane end point of <i>mSOD1^G93A</i> 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 <i>mSOD1^G93A</i> 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 <i>mSOD1^G93A</i> 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. <b>SIGNIFICANCE STATEMENT</b> 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.

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