Reduced Ca(2+) transient amplitudes may signify increased or decreased depolarization depending on the neuromodulatory signaling pathway

Neuromodulators regulate neuronal excitability and bias neural circuit outputs. Optical recording of neuronal Ca(2+) transients is a powerful approach to study the impact of neuromodulators on neural circuit dynamics. We are investigating the polymodal nociceptor ASH in Caenorhabditis elegans to better understand the relationship between neuronal excitability and optically recorded Ca(2+) transients. ASHs depolarize in response to the aversive olfactory stimulus 1-octanol (1-oct) with a concomitant rise in somal Ca(2+), stimulating an aversive locomotory response. Serotonin (5-HT) potentiates 1-oct avoidance through Gα(q) signaling, which inhibits L-type voltage-gated Ca(2+) channels in ASH. Although Ca(2+) signals in the ASH soma decrease, depolarization amplitudes increase because Ca(2+) mediates inhibitory feedback control of membrane potential in this context. Here, we investigate octopamine (OA) signaling in ASH to assess whether this negative correlation between somal Ca(2+) and depolarization amplitudes is a general phenomenon, or characteristic of certain neuromodulatory pathways. Like 5-HT, OA reduces somal Ca(2+) transient amplitudes in ASH neurons. However, OA antagonizes 5-HT modulation of 1-oct avoidance behavior, suggesting that OA may signal through a different pathway. We further show that the pathway for OA diminution of ASH somal Ca(2+) consists of the OCTR-1 receptor, the G(o) heterotrimeric G-protein, and the G-protein activated inwardly rectifying channels IRK-2 and IRK-3, and this pathway reduces depolarization amplitudes in parallel with somal Ca(2+) transient amplitudes. Therefore, even within a single neuron, somal Ca(2+) signal reduction may indicate either increased or decreased depolarization amplitude, depending on which neuromodulatory signaling pathways are activated, underscoring the need for careful interpretation of Ca(2+) imaging data in neuromodulatory studies.