Figure 6.

A schematic illustrating the influence of the C-boutons on muscle innervation and behavioral performance under various conditions. A, The interaction between the C-boutons and motor neurons (MNs) is stable in WT mice. Modulation of the motor neurons through the C-boutons occurs in a task-dependent manner. B, As motor neurons die in mSOD1^G93A mice, C-bouton activity is upregulated to compensate. This, however, seems to increase motor neuron stress and hastens muscle denervation. The result is a gradual reduction in behavioral performance that eventually leads to paralysis. The V0_c interneurons are also lost as the disease progresses. C, Silencing the C-boutons in mSOD1^G93A mice improves muscle innervation at the cost of behavioral compensation. This results in an earlier reduction in behavioral performance relative to mSOD1^G93A mice (Landoni et al., 2019). D, When C-bouton-silenced mSOD1^G93A mice undergo frequent swimming, another modulatory mechanism seems to be recruited that helps to maintain behavioral performance at the middle stage (approximately P95 to P125) and the beginning of the late stage (approximately P125+) of the disease. The mechanism at play is likely the serotonergic system, because of its known gain control of motor neurons and benefit in ALS (Turner et al., 2003; Wei et al., 2014; El Oussini et al., 2016). FF, Fast-fatigable; FR, fast-fatigue resistant; S, slow.