Escape from homeostasis: spinal microcircuits and progression of amyotrophic lateral sclerosis

Abstract

In amyotrophic lateral sclerosis (ALS), loss of motoneuron function leads to weakness and, ultimately, respiratory failure and death. Regardless of the initial pathogenic factors, motoneuron loss follows a specific pattern: the largest α-motoneurons die before smaller α-motoneurons, and γ-motoneurons are spared. In this article, we examine how homeostatic responses to this orderly progression could lead to local microcircuit dysfunction that in turn propagates motoneuron dysfunction and death. We first review motoneuron diversity and the principle of α-γ coactivation and then discuss two specific spinal motoneuron microcircuits: those involving proprioceptive afferents and those involving Renshaw cells. Next, we propose that the overall homeostatic response of the nervous system is aimed at maintaining force output. Thus motoneuron degeneration would lead to an increase in inputs to motoneurons, and, because of the pattern of neuronal degeneration, would result in an imbalance in local microcircuit activity that would overwhelm initial homeostatic responses. We suggest that this activity would ultimately lead to excitotoxicity of motoneurons, which would hasten the progression of disease. Finally, we propose that should this be the case, new therapies targeted toward microcircuit dysfunction could slow the course of ALS.

Have We Looked in the Wrong Direction for More Than 100 Years? Delayed Onset Muscle Soreness Is, in Fact, Neural Microdamage Rather Than Muscle Damage

“…It has been demonstrated that once the fatiguing muscle cannot satisfy the force generating demand from intrinsic changes, then the excitability of the motoneuron pool could be facilitated by the afferent feedback [23,24]. Brownstone et al [25] theorized that the facilitation of the premotor circuits on γ-MNs would contract the intrafusal muscle fibers out of proportion. Furthermore, focusing attention on a task secondary to any perceived weakness also increases muscle spindle sensitivity [26].…”

“…It has been shown that sustained submaximal isometric contraction ultimately leads to a progressive decline in the discharge of muscle spindle afferent [27]. According to the theory of Brownstone et al [25], the increased premotor activity and the concomitant spindle afferent input will eventually end in an escape from homeostasis in amylotrophic lateral sclerosis. We propose that the above excessive coinciding mechanical and metabolic insults impair the energy supply of the mitochondria in the sensory terminals of the muscle spindle, and this energy deficiency eventually leads to an escape from homeostasis, which we call DOMS.…”

Astrocyte-Mediated Neuromodulatory Regulation in Preclinical ALS: A Metadata Analysis

“…In fact, as discussed in more detail in the Section Astrocyte GluR as a Potential Pre-onset ALS Treatment Target, motoneurons are mathematically and functionally more susceptible to such instability (Mitchell and Lee, 2012; Irvin et al, 2015). Other recent work has also illustrated that motoneuron microcircuits are more prone to homeostatic dysregulation (Brownstone and Lancelin, 2018). Given the large variance in experimental data, small changes that were statistically insignificant may actually be physiologically significant to ALS cells.…”

Circuit-Specific Early Impairment of Proprioceptive Sensory Neurons in the SOD1G93AMouse Model for ALS

“…Consistent with that observation, reducing Ia proprioceptive muscle spindle afferents partly contributed to ␣-MN survival. Therefore, identification and characterization of circuit-specific vulnerability to disease progression in ALS (Brownstone and Lancelin, 2018) could help develop effective therapeutic strategies.…”