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

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 Cboutons 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 Cboutons 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. [ABSTRACT FROM AUTHOR]