Channel Dysfunction as the Basis for Comorbidities in Multiple Sclerosis and Depression

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system that is frequently accompanied by major depressive symptoms, which substantially worsen disease burden and quality of life. Increasing evidence suggests that this comorbidity is not solely a psychological reaction to neurological disability but may arise from shared neurobiological mechanisms. Ion channels play a central role in regulating neuronal excitability, synaptic transmission and immune cell function, and their dysregulation has emerged as a key feature of MS pathology. Demyelination and neuroinflammation induce profound alterations in the expression, distribution and function of several ion channel families, including hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, voltage-gated potassium channels such as K_v7 and two-pore domain potassium (K_2P) channels. These changes contribute to neuronal hyperexcitability, altered thalamocortical network activity and immune cell activation. Importantly, several ion channel systems implicated in MS are also associated with affective regulation, including TRPA1, ASIC1a, N-methyl-d-aspartate receptors and serotonin 5-HT3 receptors. This review summarizes current evidence linking ion channel dysfunction to both MS pathology and depression and highlights emerging pharmacological strategies targeting these channels. Understanding ion channel-mediated mechanisms may provide novel therapeutic opportunities to address both neuroinflammation and neuropsychiatric comorbidities in MS.