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Neuromodulators, such as serotonin (5-HT), alter neuronal excitability and synaptic strengths, and define different behavioral states. Neuromodulator-dependent changes in neuronal activity patterns are frequently measured using calcium reporters because calcium imaging can easily be performed on intact functioning nervous systems. With only 302 neurons, the nematode Caenorhabditis elegans provides a relatively simple, yet powerful, system to understand neuromodulation at the level of individual neurons. C. elegans hermaphrodites are repelled by 1-octanol, and the initiation of these aversive responses is potentiated by 5-HT. 5-HT acts on the ASH polymodal nociceptors that sense the 1-octanol stimulus. Surprisingly, 5-HT suppresses ASH Ca 2+ transients while simultaneously potentiating 1-octanol-dependent ASH depolarization. Here we further explore this seemingly inverse relationship. Our results show the following (1) 5-HT acts downstream of depolarization, through Gα q -mediated signaling and calcineurin, to inhibit L-type voltage-gated Ca 2+ channels; (2) the 1-octanol-evoked Ca 2+ transients in ASHs inhibit depolarization; and (3) the Ca 2+ -activated K + channel, SLO-1, acts downstream of 5-HT and is a critical regulator of ASH response dynamics. These findings define a Ca 2+ -dependent inhibitory feedback loop that can be modulated by 5-HT to increase neuronal excitability and regulate behavior, and highlight the possibility that neuromodulator-induced changes in the amplitudes of Ca 2+ transients do not necessarily predict corresponding changes in depolarization. SIGNIFICANCE STATEMENT Neuromodulators, such as 5-HT, modify behavior by regulating excitability and synaptic efficiency in neurons. Neuromodulation is often studied using Ca 2+ imaging, whereby neuromodulator-dependent changes in neuronal activity levels can be detected in intact, functioning circuits. Here we show that 5-HT reduces the amplitude of depolarization-dependent Ca 2+ transients in a C. elegans nociceptive neuron, through Gα q signaling and calcineurin but that Ca 2+ itself inhibits depolarization, likely through Ca 2+ -activated K + channels. The net effect of 5-HT, therefore, is to increase neuronal excitability through disinhibition. These results establish a novel 5-HT signal transduction pathway, and demonstrate that neuromodulators can change Ca 2+ signals and depolarization amplitudes in opposite directions, simultaneously, within a single neuron.

Serotonin Disinhibits aCaenorhabditis elegansSensory Neuron by Suppressing Ca2+-Dependent Negative Feedback

Serotonin Disinhibits aCaenorhabditis elegansSensory Neuron by Suppressing Ca²⁺-Dependent Negative Feedback