Abstract
In amyotrophic lateral sclerosis (ALS), human postmortem transcriptomics reveals a consistent shift, with downregulation of neuronal genes and upregulation of glial and inflammatory programs. This establishes a framework where inhibitory synapses and ion transport, particularly chloride channels and transporters that set the neuronal chloride gradient, are mechanistically relevant to motor system vulnerability. This review synthesizes genetic and functional evidence (2010–2025) for the involvement of chloride channels and related transporters in ALS. The evidence converges on several key mechanisms. In SOD1-ALS mouse models, there is an early, cell-type-specific deficit in glycinergic inhibition linked to reduced GLRA1 expression and synaptic loss. In skeletal muscle, ClC-1 (CLCN1) expression and chloride conductance are reduced, a deficit rescued ex vivo by PKC inhibition. In immune cells, CLIC1 is identified as a potential biomarker in peripheral blood mononuclear cells and as an inducible effector of neuroin-flammation in microglia. At the synapse, TMEM16F modulates α-motoneuron excitability at C-boutons, and its loss has sex-specific protective effects in SOD1-ALS mice. The ER-resident anion channel CLCC1 is now implicated through both rare genetic variants that impair its function and motor neuron-specific knockout models that trigger ER stress and neurodegeneration. Finally, downregulation of the KCC2 co-transporter in vulnerable motoneurons provides a mechanism for a depolarizing shift in the chloride reversal potential, impairing fast synaptic inhibition. Although coding mutations in chloride channel genes are rare, dysregulation of their expression and function converges on core ALS pathomechanisms, including excitotoxicity, neuroinflammation, and ER stress. Future research requires targeted human studies that couple genetic findings with functional readouts to clarify their therapeutic potential.