Molecular Neurobiology

, Volume 55, Issue 2, pp 1410–1418 | Cite as

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

  • Dzung Do-Ha
  • Yossi Buskila
  • Lezanne Ooi


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.


Hyperexcitability Neuronal excitability Amyotrophic lateral sclerosis Excitotoxicity Motor neurons 


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© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Illawarra Health and Medical Research Institute, School of Biological SciencesUniversity of WollongongWollongongAustralia
  2. 2.School of MedicineWestern Sydney UniversityPenrithAustralia
  3. 3.The MARCS InstituteWestern Sydney UniversityPenrithAustralia

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