Distinct co-modulation rules of synaptic and voltage-gated currents coordinates interactions of multiple neuromodulators

Abstract

Different neuromodulators usually activate distinct receptors but can have overlapping targets. Consequently, circuit output depends on neuromodulator interactions at shared targets, a poorly understood process. We explored quantitative rules of co-modulation of two principal targets: voltage-gated and synaptic ionic currents. In the stomatogastric ganglion of the crab Cancer borealis, the neuropeptides proctolin and CCAP modulate synapses of the pyloric circuit, and activate a voltage-gated current (IMI) in multiple neurons. We examined the validity of a simple dose-dependent quantitative rule that co-modulation by proctolin and CCAP is predicted by the linear sum of the individual effects of each modulator, up to saturation. We found that this rule is valid for co-modulation of synapses, but not for the activation of IMI, where co-modulation was sublinear. Given the evolutionary conservation of neuromodulator receptors and signaling pathways, such distinct rules for co-modulation of different targets are likely to be common across neuronal circuits.