Increase of hyperpolarization‐activated cyclic nucleotide‐gated current in the aberrant excitability of spinal muscular atrophy

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