Computational model of the serotonergic modulation of sensory neurons in Aplysia.

Serotonergic modulation of the sensory neurons that mediate the gill- and tail-withdrawal reflexes of Aplysia is a useful model system for studies of neuronal plasticity that contributes to learning and memory. The effects of serotonin (5-HT) are mediated, in part, via two protein kinases (protein kinase A, PKA, and protein kinase C, PKC), which in turn, modulate at least four membrane currents, including a S ("serotonin-sensitive") K(+) current (I(K, S)), a steeply voltage-dependent K(+) current (I(K-V)), a slow component of the Ca(2+)-activated K(+) current (I(K,Ca-S)), and a L-type Ca(2+) current (I(Ca-L)). The present study investigated how the modulation of these currents altered the spike duration and excitability of sensory neurons and examined the relative contributions of PKA- and PKC-mediated effects to the actions of 5-HT. A Hodgkin-Huxley type model was developed that described the ionic conductances in the somata of sensory neurons. The descriptions of these currents and their modulation were based largely on voltage-clamp data from sensory neurons. Simulations were preformed with the program SNNAP (Simulator for Neural Networks and Action Potentials). The model was sufficient to replicate empirical data that describes the membrane currents, action potential waveform and excitability as well as their modulation by application of 5-HT, increased levels of adenosine cyclic monophosphate or application of active phorbol esters. In the model, modulation of I(K-V) by PKC played a dominate role in 5-HT-induced spike broadening, whereas the concurrent modulation of I(K,S) and I(K,Ca-S) by PKA primarily accounted for 5-HT-induced increases in excitability. Finally, simulations indicated that a PKC-induced increase in excitability resulted from decreases of I(K,S) and I(K,Ca-S), which was likely the indirect result of cross-talk between the PKC and PKA systems. The results provide several predictions that warrant additional experimental investigation and illustrate the importance of considering indirect as well as direct effects of modulatory agents on the modulation of membrane currents.