Neuromodulation of zebrafish primary motoneuron firing is shaped by developmental changes in the M-current

Movements during development are refined through the ongoing maturation of the spinal circuits that mediate them. In many vertebrates, including zebrafish, this maturation process involves neuromodulators such as acetylcholine, serotonin, and dopamine; however, the targets of this neuromodulation remain largely unknown. Recent work has revealed distinct developmental dynamics of the non-inactivating subthreshold potassium current - the M-current - in primary motoneurons of larval zebrafish. Considering that neuromodulators play a role in the maturation of locomotor control in larval zebrafish, we asked whether neuromodulators might target the M-current in primary motoneurons during development. Our patch-clamp experiments in primary motoneurons of zebrafish aged 3 to 5 days post-fertilization (dpf) reveal distinct modulation of the M-current by serotonin and acetylcholine that is age-dependent. Our data demonstrates an inhibitory influence of serotonin signaling via 5HT1A receptors that promotes repetitive firing in primary motoneurons specifically at 3 dpf. We also show that acetylcholine, likely via M2/M4 receptors, enhances the M-current and limits repetitive firing in primary motoneurons but does so only after 3 dpf. Modulation of the M-current in primary motoneurons was not observed across all neuromodulators as dopamine had no effect at any age. Considering that the M-current transiently peaks at 3 dpf and is reduced at 4 and 5 dpf, our findings suggest that the developmental changes in this current can shape how neuromodulators modulate firing properties of primary motoneurons. Key pointsO_LIThe amplitude of the M-current is subject to modulation by several neuromodulators such as acetylcholine and serotonin C_LIO_LISerotonin via 5HT1A inhibits the M-current in primary motoneurons at 3 dpf C_LIO_LIMuscarinic agonist enhances the M-current in primary motoneurons after 3 dpf C_LIO_LINeuromodulation of motoneuron firing properties by 5-HT1A and muscarinic agonist is consistent with modulation of the M-current C_LI