Computational model of the serotonergic modulation of sensory neurons in Aplysia

Serotonergic modulation of the sensory neurons that mediate the gill-and ta il-withdrawal reflexes of Aplysia is a useful model system for studies of n euronal plasticity that contributes to learning and memory. The effects of serotonin (5-HT) are mediated, in part, via two protein kinases (protein ki nase A, PKA, and protein kinase C, PKC), which in turn, modulate at least f our membrane currents, including a S ("serotonin-sensitive") K+ current (I- K,(S)), a steeply voltage-dependent K+ current (IK-V), a slow component of the Ca2+ activated K+ current (I-K,I-Ca-S), and a L-type Ca2+ current (ICa- L). The present study investigated how the modulation of these currents alt ered the spike duration and excitability of sensory neurons and examined th e 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 c onductances in the somata of sensory neurons. The descriptions of these cur rents and their modulation were based largely on voltage-clamp data from se nsory neurons. Simulations were preformed with the program SNNAP (Simulator for Neural Networks and Action Potentials). The model was sufficient to re plicate empirical data that describes the membrane currents, action potenti al 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 IK-V, by PKC played a do minate role in 5-HT-induced spike broadening, whereas the concurrent modula tion of I-K,I-S and I-K,I-Ca-S by PKA primarily accounted for 5-HT-induced increases in excitability. Finally, simulations indicated that a PKC-induce d increase in excitability resulted from decreases of I-K,I-S and I-K,I-Ca- S which was likely the indirect result of cross-talk between the PKC and PK A systems. The results provide several predictions that warrant additional experimental investigation and illustrate the importance of considering ind irect as well as direct effects of modulatory agents on the modulation of m embrane currents.