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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\u2010activated cyclic nucleotide\u2010gated (HCN) channels, voltage\u2010gated potassium channels such as K\n                    <jats:sub>v<\/jats:sub>\n                    7 and two\u2010pore domain potassium (K\n                    <jats:sub>2P<\/jats:sub>\n                    ) 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                    <jats:italic>N<\/jats:italic>\n                    \u2010methyl\u2010\n                    <jats:sc>d<\/jats:sc>\n                    \u2010aspartate receptors and serotonin 5\u2010HT3 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\u2010mediated mechanisms may provide novel therapeutic opportunities to address both neuroinflammation and neuropsychiatric comorbidities in MS.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70273","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T08:12:16Z","timestamp":1780992736000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Channel Dysfunction as the Basis for Comorbidities in Multiple Sclerosis and Depression"],"prefix":"10.1002","volume":"359","author":[{"given":"Nicole","family":"Rychlik","sequence":"first","affiliation":[{"name":"Department of Neurology University Hospital M\u00fcnster M\u00fcnster Germany"},{"name":"Institute of Physiology I, University of M\u00fcnster M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kay","family":"J\u00fcngling","sequence":"additional","affiliation":[{"name":"Institute of Physiology I, University of M\u00fcnster M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven G.","family":"Meuth","sequence":"additional","affiliation":[{"name":"Department of Neurology University Hospital M\u00fcnster M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5263-8183","authenticated-orcid":false,"given":"Thomas","family":"Budde","sequence":"additional","affiliation":[{"name":"Institute of Physiology I, University of M\u00fcnster M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8931-019X","authenticated-orcid":false,"given":"Marta","family":"M\u00e9ndez\u2010Couz","sequence":"additional","affiliation":[{"name":"Institute of Physiology I, University of M\u00fcnster M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"e_1_2_16_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbih.2022.100484"},{"key":"e_1_2_16_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0404.2004.00257.x"},{"key":"e_1_2_16_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2016.11.067"},{"key":"e_1_2_16_5_1","doi-asserted-by":"crossref","unstructured":"S. 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