Neurophysiological Mechanisms Underlying Cortical Hyper-Excitability in Amyotrophic Lateral Sclerosis: A Review

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neuromotor disease characterized by the loss of upper and lower motor neurons (MNs), resulting in muscle paralysis and death. Early cortical hyper-excitability is a common pathological process observed clinically and in animal disease models. Although the mechanisms that underlie cortical hyper-excitability are not completely understood, the molecular and cellular mechanisms that cause enhanced neuronal intrinsic excitability and changes in excitatory and inhibitory synaptic activity are starting to emerge. Here, we review the evidence for an anterograde glutamatergic excitotoxic process, leading to cortical hyper-excitability via intrinsic cellular and synaptic mechanisms and for the role of interneurons in establishing disinhibition in clinical and experimental settings. Understanding the mechanisms that lead to these complex pathological processes will likely produce key insights towards developing novel therapeutic strategies to rescue upper MNs, thus alleviating the impact of this fatal disease.

Subject-specific features of excitation/inhibition profiles in neurodegenerative diseases

“…Considering the biophysical meaning of TVB parameters, cluster 1 was mainly characterized by overexcitation and was more frequent in Healthy Controls and Amyotrophic Lateral Sclerosis. As well as being consistent with the fact that hyperexcitability is a well-known feature of Amyotrophic Lateral Sclerosis patients (Brunet et al, 2020;Pradhan and Bellingham, 2021), the presence of some Healthy Controls subjects in this cluster is not surprising. Indeed, the effect of aging on the glutamatergic system is currently under investigation (Segovia et al, 2001), and even if glutamate is mostly reported to decrease with age Monteverdi et al 10.3389/fnagi.2022.868342 (Roalf et al, 2020), age-related effects on glutamatergic release and uptake processes and NMDA receptors activation could be differentially modulated in some healthy subjects.…”

“…Finally, Amyotrophic Lateral Sclerosis patients were characterized by an increased J NMDA , which is in line with the cortical hyperexcitability frequently reported in this pathological condition (Pradhan and Bellingham, 2021).…”

“…This high G-value could be due to an increased strength of longrange connectivity or increased synchrony between nodes. It is worth noting that cluster 2 was more common in pathological conditions than in Healthy Controls, and this is in line with the frequent observation of hyperexcitation and hypersynchrony in Alzheimer's Disease (Henstridge et al, 2019;Maestú et al, 2019, Maestú et al, 2021, Frontotemporal Dementia (Hughes et al, 2018;Benussi et al, 2019), and Amyotrophic Lateral Sclerosis (Dukic et al, 2019;Pradhan and Bellingham, 2021). Cluster 3 was the most related to Healthy Controls, while the number of patients was marginal (0 for the Alzheimer's Disease group).…”

“…Indeed, hyperexcitation is thought to play a pivotal role in Alzheimer Disease, Frontotemporal Dementia, and Amyotrophic Lateral Sclerosis pathogenesis (Benussi et al, 2019;Maestú et al, 2021; Abbreviations: expFC, experimental Functional Connectivity; FC, Functional Connectivity; PCC, Pearson Correlation Coefficient; SC, Structural Connectivity; simFC, simulated Functional Connectivity; TVB, The Virtual Brain. Pradhan and Bellingham, 2021), but multiform and sometimes contradictory results based on empirical observations make it difficult to gain an overall agreement on the neural mechanisms and the evolution of hyperexcitation over the course of the disease. In addition, despite some controversies, increasing findings are supporting GABAergic remodeling as an important feature of Alzheimer's Disease condition (Bi et al, 2020).…”

Cytoplasmic Human TDP-43 Mislocalization Induces Widespread Dendritic Spine Loss in Mouse Upper Motor Neurons

“…Spine loss and dendrite pathology is observed in upper motor neurons of ALS patient post-mortem tissue [16,41]. This spine loss has been replicated in preclinical models and shown to be a consistent feature of familial mouse models of ALS at symptomatic time points [42]. The most widely characterized model of familial ALS, the mutant SOD1 G93A mouse model, demonstrates progressive spine loss [43].…”