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 mSOD1(G93A) 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 mSOD1(G93A) mice to mSOD1(G93A) mice with genetically silenced C-boutons [mSOD1(G93A); Dbx1::cre; ChAT(fl/fl) (mSOD1(G93A)/C-off)], we show that the C-boutons do not influence the humane end point of mSOD1(G93A) mice; however, our histologic analysis shows that C-bouton silencing significantly improves fast-twitch musde innervation over time. Using immunohistology, we also show that the C-boutons are active in a task-dependent manner, and that symptomatic mSOD1(G93A) 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 mSOD1(G93A) 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.

Automated summary

ALS is a neurodegenerative disease resulting in progressive motor neuron death and typically fatal within 5 years of diagnosis. Research indicates that silencing C-boutons in ALS mouse models can improve muscle innervation and behavioral capabilities, suggesting that manipulating these synapses in combination with targeted training programs could be beneficial for ALS patients, leading to improved mobility and quality of life.