Presynaptic Modulation of Voltage-dependent Ca2+ Current: Mechanism for Behavioral Sensitization in Aplysia Californica

Behavioral sensitization of the gill-withdrawal reflex of Aplysia is the result of a prolonged increase in transmitter release from the presynaptic terminals of sensory neurons. Earlier work suggested that this presynaptic facilitation might be mediated by a serotonin-sensitive adenylate cyclase in the sensory neuron terminals. Here we present evidence that presynaptic facilitation results from a cyclic AMP-dependent increase in the calcium current that underlies action potentials in the sensory neurons. The action potentials of sensory neuron cell bodies have, in addition to a sodium current, a calcium current that is enhanced by blocking the opposing potassium current with tetraethylammonium. Under these conditions, the action potentials show a slowly repolarizing plateau that follows the Nernst potential for a calcium electrode and serves as a sensitive assay for changes in calcium current. Stimulation of the pathway that mediates sensitization, incubation with serotonin or phosphodiesterase inhibitors, or intracellular injection of cyclic AMP produces an increase in the calcium plateau in the presence of tetraethylammonium. In addition, both before and after sensitizing stimulation, the duration of the plateau potential parallels transmitter release as measured by the amplitude of monosynaptic excitatory postsynaptic potentials evoked in the motor neurons by intracellular stimulation of single sensory neurons. These results are consistent with the idea that presynaptic facilitation is caused by a cyclic AMP-mediated increase in a voltage-sensitive calcium current in sensory neuron presynaptic terminals. This synaptic action is novel in that it can produce little or no change in the resting potential, is of long duration, and exerts its influence directly on a conductance triggered by the action potential, rather than on non-voltage-sensitive conductances, as is typical of conventional synaptic actions.