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 non-inactivating subthreshold potassium current – the M-current – is well known for being a target for neuromodulation. 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 days post-fertilization (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 primary motoneurons of zebrafish. 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 PIP 2 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. Significance Statement Neuromodulation of spinal circuits adjusts motor activity. Spinal circuits in zebrafish are subject to neuromodulation during developmental and adult stages, though the targets of this neuromodulation remain to be identified. We demonstrate that during development, acetylcholine and serotonin can modify the firing properties of primary motoneurons that innervate fast muscle fibers, through the modulation of the M-current. The amplitude of this current in primary motoneurons changes dynamically during zebrafish development. We show that the direction of modulation of the M-current reverses as its basal amplitude peaks and decays between three and five days post-fertilization, revealing dynamic control over the amplitude of the M-current in primary motoneurons as zebrafish transition from relying primarily on crude, ballistic movements to more coordinated swimming.
Gaudreau et al. (Fri,) studied this question.