HCN channels modulate the medium afterhyperpolarization and adjust the firing gain of fast alpha motoneurons in mice

Abstract

Motoneuron subtypes exhibit distinct firing properties that are critical for the graded control of muscle force. A key determinant of these differences is the medium afterhyperpolarization (mAHP), which shapes discharge rate and firing gain. While subtype-specific variation in mAHP properties has traditionally been attributed to differences in small-conductance calcium-activated potassium (SK) channel expression, emerging evidence suggests that additional conductances may contribute. Here, we investigated the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in regulating the mAHP and excitability of mouse spinal motoneurons during postnatal development. Using whole-cell patch-clamp recordings, we show that, by the onset of the third postnatal week, an h current (Ih) is active at resting potential in fast motoneurons and is correlated with the amplitude of the mAHP. Pharmacological blockade of HCN channels with ZD7288 increased mAHP amplitude in fast but not slow motoneurons, without affecting mAHP duration, indicating a subtype-specific contribution to mAHP amplitude. In line with the mAHP regulating firing gain, ZD7288 also reduced firing gain in fast but not slow motoneurons. These findings support a contribution of HCN channel activity to the regulation of mAHP amplitude and firing gain in fast motoneurons, highlighting a potential interaction between Ih and SK channel-dependent mechanisms in shaping motoneuron excitability. Key PointsO_LIThe amplitude of the medium afterhyperpolarization (mAHP) is negatively correlated with h-current (Ih) amplitude measured near resting potential in mouse lumbar motoneurons. C_LIO_LIPharmacological blockade of HCN channels selectively increases mAHP amplitude in fast, delayed firing alpha motoneurons, with no effect observed in slow, immediate firing alpha motoneurons. C_LIO_LIInhibition of HCN channels reduces firing gain in fast motoneurons, while slow motoneurons remain unaffected. C_LIO_LIHCN channels regulate firing gain in fast motoneurons, at least in part, through modulation of mAHP amplitude. C_LI