Increase of hyperpolarization-activated cyclic nucleotide-gated current in the aberrant excitability of spinal muscular atrophy
Journal
Annals of Neurology
Journal Volume
83
Journal Issue
3
Pages
494-507
ISSN
0364-5134
Date Issued
2018-03
Author(s)
Abstract
Objective: The pathophysiology of spinal muscular atrophy (SMA) is still unclear. Methods: 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-cell patch-clamp recording were used for the identified hypothesis. Results: The nerve excitability test in SMA patients showed increased inward rectification in the current-threshold relationship and increased overshoot after hyperpolarizing threshold electrotonus, which indicates increased hyperpolarization-activated cyclic nucleotide-gated (HCN) current; these findings correlated with disease severity. Increased inward rectification in the current-threshold 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-clamp 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. Interpretation: This study shows that increased HCN current underlies the pathophysiology of SMA and can be a novel non-SMN target for SMA therapy. Ann Neurol 2018;83:494–507. ? 2018 American Neurological Association
SDGs
Other Subjects
4 (n ethyl n phenylamino) 1,2 dimethyl 6 (methylamino)pyrimidinium chloride; hyperpolarization activated cyclic nucleotide gated channel; hyperpolarization activated cyclic nucleotide gated channel 1; hyperpolarization activated cyclic nucleotide gated channel 2; unclassified drug; Hcn1 protein, mouse; Hcn2 protein, mouse; hyperpolarization activated cyclic nucleotide gated channel; potassium channel; action potential amplitude; adult; animal cell; animal experiment; animal model; animal tissue; Article; controlled study; current density; disease severity; drug mechanism; human; hyperpolarization; ion current; male; middle aged; motoneuron; motor performance; mouse; nerve excitability; neuromuscular junction; newborn; nonhuman; pathogenesis; polymerase chain reaction; priority journal; protein expression; quantitative analysis; sciatic nerve; spinal cord; spinal muscular atrophy; voltage clamp technique; Western blotting; young adult; action potential; adolescent; animal; female; genetics; knockout mouse; pathophysiology; physiology; spinal muscular atrophy; transgenic mouse; Action Potentials; Adolescent; Adult; Animals; Female; Humans; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Male; Mice; Mice, Knockout; Mice, Transgenic; Muscular Atrophy, Spinal; Potassium Channels; Young Adult
Type
journal article