Impairments in Motor Neurons, Interneurons and Astrocytes Contribute to Hyperexcitability in ALS: Underlying Mechanisms and Paths to Therapy

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of motor neurons leading to progressive paralysis and death. Using transcranial magnetic stimulation (TMS) and nerve excitability tests, several clinical studies have identified that cortical and peripheral hyperexcitability are among the earliest pathologies observed in ALS patients. The changes in the electrophysiological properties of motor neurons have been identified in both sporadic and familial ALS patients, despite the diverse etiology of the disease. The mechanisms behind the change in neuronal signalling are not well understood, though current findings implicate intrinsic changes in motor neurons and dysfunction of cells critical in regulating motor neuronal excitability, such as astrocytes and interneurons. Alterations in ion channel expression and/or function in motor neurons has been associated with changes in cortical and peripheral nerve excitability. In addition to these intrinsic changes in motor neurons, inhibitory signalling through GABAergic interneurons is also impaired in ALS, likely contributing to increased neuronal excitability. Astrocytes have also recently been implicated in increasing neuronal excitability in ALS by failing to adequately regulate glutamate levels and extracellular K concentration at the synaptic cleft. As hyperexcitability is a common and early feature of ALS, it offers a therapeutic and diagnostic target. Thus, understanding the underlying pathways and mechanisms leading to hyperexcitability in ALS offers crucial insight for future development of ALS treatments.

The sigma‐1 receptor behaves as an atypical auxiliary subunit to modulate the functional characteristics of Kv1.2 channels expressed in HEK293 cells

“…; Do‐Ha et al. ). Moreover, reduced delayed rectifier potassium channel current is a mechanism of hyperexcitability in ALS patient‐derived motor neurons (Wainger et al.…”

“…A recurrent "loss-of-function" mutation in KCNA2 was recently identified which results in hereditary spastic paraplegia (Helbig et al 2016). Hyperexcitability has also been observed in amyotrophic lateral sclerosis (ALS) patients Do-Ha et al 2018;Fogarty 2018), with the degree of hyperexcitability correlating with patient survival (Kanai et al 2012). This may be due to a mechanism involving decreased activity of delayed rectifier potassium channels Do-Ha et al 2018).…”

“…Moreover, simply increasing expression levels of the Sig‐1R leads to a change in the activation gating state of Kv1.2, from predominantly “fast” to predominantly “slow.” These effects are not observed in the presence of Sig‐1R‐E102Q, suggesting that aberrant Kv1.2 channel modulation may underlie neuronal hyperexcitability observed in ALS (Do‐Ha et al. ; Fogarty ).…”

Optogenetic manipulation of astrocytes from synapses to neuronal networks: A potential therapeutic strategy for neurodegenerative diseases

“…Furthermore, the communication between astrocytes and neurons not only plays a role in regulating synaptic function, but also in dominating the activity of neural networks. Astrocytes have been shown to integrate into a variety of inhibitory neural networks which are compromised in NDs (Deemyad, Luthi, & Spruston, ; Do‐Ha, Buskila, & Ooi, ). Does the impaired communication between the astrocytes and the neurons result in the inhibitory neural dysfunction in the NDs?…”

“…integrate into a variety of inhibitory neural networks which are compromised in NDs (Deemyad, Luthi, & Spruston, 2018;Do-Ha, Buskila, & Ooi, 2018). Does the impaired communication between the astrocytes and the neurons result in the inhibitory neural dysfunction in the NDs?…”