Ion channel dysfunction and altered motoneuron excitability in ALS

Dysregulated excitability is a hallmark of Amyotrophic Lateral Sclerosis (ALS) pathology both in ALS research models and in clinical settings. This primarily results from the dysfunction of Na⁺, K⁺, and Ca²⁺ ion channels responsible for maintaining neuronal thresholds and executing signal transduction or synaptic transmission. The exact dysfunction that each of these ion channel currents display in ALS pathology can vary between different ALS models, mainly induced pluripotent stem cell (iPSC) derived human motoneurons and ALS mouse models. Moreover, results can vary further across ALS mutations and between different developmental periods of these disease models. This review attempts to gather observations regarding ion channel dysfunction contributing to both hyperexcitable and hypoexcitable phenotypes in ALS motoneurons both in vivo and in vitro, so as to assess their potential as therapeutic targets.