Potential contribution of spinal interneurons to the etiopathogenesis of amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) consists of a group of adult-onset fatal and incurable neurodegenerative disorders characterized by the progressive death of motor neurons (MNs) throughout the central nervous system (CNS). At first, ALS was considered to be an MN disease, caused by cell-autonomous mechanisms acting specifically in MNs. Accordingly, data from ALS patients and ALS animal models revealed alterations in excitability in multiple neuronal populations, including MNs, which were associated with a variety of cellular perturbations such as protein aggregation, ribonucleic acid (RNA) metabolism defects, calcium dyshomeostasis, modified electrophysiological properties, and autophagy malfunctions. However, experimental evidence rapidly demonstrated the involvement of other types of cells, including glial cells, in the etiopathogenesis of ALS through non-cell autonomous mechanisms. Surprisingly, the contribution of pre-motor interneurons (INs), which regulate MN activity and could therefore critically modulate their excitability at the onset or during the progression of the disease, has to date been severely underestimated. In this article, we review in detail how spinal pre-motor INs are affected in ALS and their possible involvement in the etiopathogenesis of the disease.

Keywords: amyotrophic lateral sclerosis; motor neurons; neurodegenerative disease; non-cell autonomous mechanisms; pre-motor interneurons; spinal cord.

Figure 1

Diversity and connectivity of spinal ventral neuronal populations. A schematic representation of an embryonic transverse hemisection (A) or the ventral half of an adult transverse section (B) in the spinal cord is shown here. Ventral is to the bottom, dorsal is to the top. (A) The six most ventral progenitor domains (dp6, p0, p1, p2, pMN, and p3) and each cardinal neuronal population (dI6, V0, V1, V2, and V3 interneurons [INs], and motor neurons [MN]) arising from their respective progenitor domains. The other half of the spinal cord, as well as the dorsal progenitor domains and neuronal populations, are not represented. (B) The MNs and the main pre-motor IN populations involved in the spinal motor circuitry and their known connectivity are represented by colored bubbles (cell body localization) and arrows (projections). For clarity, excitatory or neuromodulatory populations are represented on the left hemicord, and inhibitory populations are represented on the right hemicord, although all these populations are evidently present on both sides. Hb9-IN (the origin of which remains elusive) and V0g connectivity are not precisely known. RC: Renshaw cells (V1 IN subset).

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.

Figure 3

Spinal neuronal excitatory circuitry and its fate in ALS. Excitatory interneurons (INs) are represented in green, and motor neurons (MNs) are represented in gray. Altered INs and MNs are represented in light green and light gray, respectively. Degenerative cells are represented by dotted lines on the cell body and projections. (A) Excitatory circuitry in a non-pathological situation. (B) Early increase in activity of the excitatory circuitry before the apparition of the first symptoms. This change might preserve motor activity despite low-noise early MN alterations but may result in excitotoxicity for the MNs. The hyperexcitability of the MNs is represented by spikes on the cell body. (C) Alterations of the excitatory circuitry during the symptomatic phase of the disease. It is still unclear whether degeneration of MNs occurs before or after degeneration of excitatory INs and if one is causative of the other.

Figure 4

Spinal neuronal cholinergic circuitry and its fate in ALS. Cholinergic interneurons (INs) are represented in yellow, and motor neurons (MNs) in gray. Altered INs and MNs are represented in light yellow and light gray, respectively. Degenerative cells are represented by dotted lines on the cell body and projections. (A) Cholinergic circuitry in a non-pathological situation. (B) Early increase in activity of the cholinergic circuitry before the apparition of the first symptoms. This modified activity might preserve motor activity despite low-noise early MN alterations but may result in excitotoxicity for the MNs. The hyperexcitability of the MNs is represented by spikes on the cell body. This hyperexcitability may contribute to MN excitotoxicity. (C) Alterations of the cholinergic circuitry during the symptomatic phase of the disease. It is still unclear whether degeneration of MN occurs before or after degeneration of cholinergic INs and if one is causative of the other.