Heterosynaptic enhancement of transmitter release is potentially very important for neuronal computation, yet, to our knowledge, no prior study has shown that stimulation of one neuron directly enhances release from an interneuron. Here, we demonstrate that in the marine mollusk Tritonia diomedea, the serotonergic dorsal swim interneurons (DSIs) heterosynaptically increase the amount of transmitter released from another interneuron, C2. Stimulation of a single DSI at physiological firing frequencies increases the size of synaptic potentials evoked by C2. This increase in synaptic efficacy is correlated with an increase in homosynaptic paired-pulse facilitation by C2. Thus, it is likely to be due to an enhancement of transmitter release from C2, rather than a postsynaptic action on the followers of C2. This is further supported by the fact that DSI stimulation enhances the strengths of all chemical synapses made by C2 within the swim network, regardless of their sign. Furthermore, DSI enhances the amplitude of C2 synaptic potentials recorded in neurons that DSI itself does not synapse with. Finally, DSI differentially modulates different synaptic inputs to the same postsynaptic target; while increasing C2- evoked EPSPs it simultaneously decreases the size of EPSPs evoked by other DSIs. The heterosynaptic facilitation of C2 synaptic potentials by DSI is not caused by a simple depolarization of C2, but may be a direct action on the transmitter release mechanism. This neuromodulatory effect, which is intrinsic to the circuitry of the central pattern generator for escape swimming in Tritonia, may be important for self-reconfiguration of the swim motor network.