Modulation of afterhyperpolarization (AHP) represents an important mechanism by which excitability of a neuron can be regulated. In the leech brain, sensitization enhances excitability of the S-cell, an interneuron thought to play an important role in this form of non-associative learning. This increase in excitability is serotonin (5HT)-dependent, but it is not known whether changes in AHP contribute to 5HT-mediated enhancement of excitability. Therefore, electrophysiological recordings and computational modeling were used to determine whether 5HT enhances excitability via modulation of AHP. 5HT reduced S-cell AHP and this decrease in the AHP corresponded with an increase in excitability. Little or no AHP is observed in the presence of Ca²⁺-free saline, suggesting the involvement of Ca²⁺-dependent K⁺ channels. Furthermore, AHP amplitude decreased following treatment with drugs (tubocurare and charybdotoxin) that block Ca²⁺-dependent K⁺ channel activity. The S-cell also exhibits an afterdepolarization (ADP) which is usually masked by the AHP and was inhibited by the Na⁺ channel blocker, saxitoxin. A model of the S-cell AHP was constructed using two Ca²⁺-dependent K⁺ currents and a Na⁺ driven ADP current. Reduction of the model conductances underlying the AHP to mimic the effects of 5HT was sufficient to enhance excitability. These findings were confirmed in occlusion experiments in which pretreatment with tubocurare was able to block 5HT-mediated decreases in mAHP levels and increases in excitability. These data show that modulation of S-cell AHP can contribute to 5HT-mediated increases in excitability and that the S-cell afterpotential is due to the combined effects of AHP- and ADP-producing currents.