Developmental Changes to the M-Current Shape the Direction of Its Neuromodulation in Zebrafish Motoneurons

Movements during development are refined through ongoing maturation of the spinal circuits that mediate them. In many vertebrates, including zebrafish, this maturation process involves neuromodulators; however, targets of this neuromodulation remain largely unknown. The noninactivating subthreshold potassium current-the M-current-is well known for being a neuromodulatory target. We asked whether neuromodulators might target the M-current in primary motoneurons during development. Our patch-clamp experiments in primary motoneurons of zebrafish (unknown sex) aged 3 to 5 d postfertilization (dpf) reveal distinct modulation of the M-current by acetylcholine and serotonin. Neuromodulation of the M-current was found to change during development with the effects of neuromodulation reflecting the relative levels of the M-current in primary motoneurons at different ages. Indeed, recent work has revealed that the M-current transiently peaks at 3 dpf and is reduced at 4 and 5 dpf in zebrafish primary motoneurons. Our data demonstrates an inhibitory influence of serotonin signaling via 5HT_1A receptors that promotes repetitive firing in primary motoneurons specifically at 3 dpf. 5HT_1A agonism also increases motor output during evoked swimming at that age. We also show that acetylcholine enhances the M-current via M2 receptors and limits repetitive firing in primary motoneurons most prominently at 4 and 5 dpf but not at 3 dpf. Pharmacological modulation of PIP₂ suggests that neuromodulation of the M-current in primary motoneurons may act through this signaling pathway. Our findings suggest that the developmental changes in the M-current shape the direction of neuromodulatory control over primary motoneuron firing and, by consequence, motor activity.