Figure 2.

Spinal neuronal inhibitory circuitry and its fate in ALS. Inhibitory interneurons (INs) are represented in red, and motor neurons (MNs) in gray. Altered INs and MNs are represented in light red and light gray, respectively. (A) Inhibitory circuitry in a non-pathological situation. (B) Early alteration of the inhibitory circuitry before the apparition of the first symptoms. The decrease in glycinergic signaling and in the recurrent inhibition loop ensured by Renshaw cells might act as compensatory mechanisms that preserve motor activity despite low-noise early MN alterations before deleterious breakdown of the circuitry. This possibly results in MN hyperexcitability, represented by spikes on the cell body. This hyperexcitability may contribute to MN excitotoxicity. Panel B summarizes in a single scheme the different alterations involving spinal inhibitory INs, including Renshaw cells, whatever their chronology (for more details, see the proposed working hypothesis in the last section of this article). (C) Alterations of the inhibitory circuitry during the symptomatic phase of the disease. Degenerative cells are represented by dotted lines on the cell body and projections. It is still unclear whether degeneration of MNs occurs before or after degeneration of inhibitory INs and if one is causative of the other. RC, Renshaw cells.