Cortical Circuit Dysfunction as a Potential Driver of Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects selected cortical and spinal neuronal populations, leading to progressive paralysis and death. A growing body of evidences suggests that the disease may originate in the cerebral cortex and propagate in a corticofugal manner. In particular, transcranial magnetic stimulation studies revealed that ALS patients present with early cortical hyperexcitability arising from a combination of increased excitability and decreased inhibition. Here, we discuss the possibility that initial cortical circuit dysfunction might act as the main driver of ALS onset and progression, and review recent functional, imaging and transcriptomic studies conducted on ALS patients, along with electrophysiological, pathological and transcriptomic studies on animal and cellular models of the disease, in order to evaluate the potential cellular and molecular origins of cortical hyperexcitability in ALS.

Absence of Subcerebral Projection Neurons Is Beneficial in a Mouse Model of Amyotrophic Lateral Sclerosis

“…Although the corticomotoneuronal system has undergone major modifications with evolution, 4 corticothalamic and SubCerPN populations are remarkably well conserved between mice and humans, as opposed to the commissural and associative projection neuron populations 35 . Further support for the appropriateness of rodents to study the cortical contributions to ALS is provided by their ability to recapitulate CSN or SubCerPN degeneration 8 . In the Sod1 G86R mouse model, CSN precedes MN degeneration and NMJ denervation 11 .…”

“…Together, the two studies suggest that absence of diseased CSN or instead maintenance of genetically corrected CSN might be equally beneficial and that Sod1/SOD1 mutant transgene‐expressing CSN might be detrimental to their downstream targets. Yet, it is worth mentioning that AAV9 is likely to have targeted all types of cortical excitatory and inhibitory neurons, potentially contributing to correct cortical circuit dysfunctions such as those reported in Sod1 G93A and TDP‐43 A315T mouse models of ALS 8 . Cell type‐specific genetic ablation experiments could provide further information on the contribution of individual neuronal and glial populations to cortical circuit dysfunction and consequences for corticofugal targets.…”

“…It is possible that this beneficial effect arose from targeting cortical IN that modulate the excitability and activity of corticofugal neurons 41 . Given the reported alterations in excitability of cortical neuron populations in different mouse models of the disease, 8,42 comparison between silencing and genetic ablation of adult corticofugal neurons would be particularly informative to gain a better understanding of the mechanism by which these neurons might contribute to disease onset and progression. Finally, deep molecular analysis of CSN dysfunction in ALS 11 might in the future provide a better understanding of the role of the cerebral cortex and its outputs to ALS and potentially unravel new therapeutic targets.…”

“…In rodents, as in humans, corticofugal projections arise from two populations: corticothalamic projection neurons and subcerebral projection neurons (SubCerPN) that include the disease‐relevant CSN 9,10 . Although major differences exist between primates and rodents regarding the route of the corticospinal tract and the connectivity of CSN onto alpha motoneurons, many mouse models of ALS recapitulate CSN or SubCerPN degeneration (reviewed by Brunet and colleagues 8 ). Likewise, we recently showed that Sod1 G86R mice display presymptomatic CSN degeneration and a somatotopic relationship between CSN and spinal motoneuron degeneration, 11 as reported in ALS patients 12 …”

Exciting Complexity: The Role of Motor Circuit Elements in ALS Pathophysiology

“…Moreover, ALS patients have increased levels of norepinephrine in blood and the cerebrospinal fluid (CSF) (Ziegler et al, 1980), which could synergize with glutamate and increase neuronal excitation (Mather et al, 2016). For a more detailed description on the impact of altered neuromodulation in motor cortex in ALS see Brunet et al (2020). Together, these studies emphasize that circuit elements other than the mainly affected UMN are strongly altered likely already early in the disease.…”