{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T15:44:59Z","timestamp":1790523899858,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,3,10]],"date-time":"2018-03-10T00:00:00Z","timestamp":1520640000000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["105\u20102628\u2010B\u2010002\u2010012\u2010MY3"],"award-info":[{"award-number":["105\u20102628\u2010B\u2010002\u2010012\u2010MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005762","name":"National Taiwan University Hospital","doi-asserted-by":"publisher","award":["105\u2010N3292"],"award-info":[{"award-number":["105\u2010N3292"]}],"id":[{"id":"10.13039\/501100005762","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005762","name":"National Taiwan University Hospital","doi-asserted-by":"publisher","award":["106\u2010N3646"],"award-info":[{"award-number":["106\u2010N3646"]}],"id":[{"id":"10.13039\/501100005762","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The pathophysiology of spinal muscular atrophy (SMA) is still unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The nerve excitability test in SMA patients and a mouse model of SMA was carried out to explore the pathophysiology of nodal and internodal currents, and quantitative PCR, western blotting, and whole\u2010cell patch\u2010clamp recording were used for the identified hypothesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The nerve excitability test in SMA patients showed increased inward rectification in the current\u2010threshold relationship and increased overshoot after hyperpolarizing threshold electrotonus, which indicates increased hyperpolarization\u2010activated cyclic nucleotide\u2010gated (HCN) current; these findings correlated with disease severity. Increased inward rectification in the current\u2010threshold relationship was reproducible in a mouse model of mild SMA, and the abnormality preceded the decline of compound motor action potential amplitudes. Furthermore, quantitative PCR of spinal cord tissues and western blotting of the spinal cord and sciatic nerves showed increased HCN1 and HCN2 expression in SMA mice, and voltage\u2010clamp recording in dissociated spinal motor neurons from SMA mice also showed increased HCN current density. Treatment with ZD7288, an HCN channel blocker, also reduced early mortality, improved motor function, and restored neuromuscular junction architecture in a mouse model of severe SMA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>This study shows that increased HCN current underlies the pathophysiology of SMA and can be a novel non\u2010SMN target for SMA therapy. Ann Neurol 2018;83:494\u2013507<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.25168","type":"journal-article","created":{"date-parts":[[2018,2,2]],"date-time":"2018-02-02T22:58:49Z","timestamp":1517612329000},"page":"494-507","source":"Crossref","is-referenced-by-count":7,"title":["Increase of hyperpolarization\u2010activated cyclic nucleotide\u2010gated current in the aberrant excitability of spinal muscular atrophy"],"prefix":"10.1002","volume":"83","author":[{"given":"Hsing\u2010Jung","family":"Lai","sequence":"first","affiliation":[{"name":"Department of Neurology National Taiwan University Hospital and National Taiwan University College of Medicine Taipei Taiwan"},{"name":"Institute of Physiology National Taiwan University Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien\u2010Lin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology National Taiwan University Hospital and National Taiwan University College of 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