Purpose: Preclinical data have suggested that selective serotonin reuptake inhibitors (SSRIs) may have anticonvulsant properties, and some SSRIs are known to modulate ion channels in vitro. We screened citalopram, fluoxetine, and sertraline for anticonvulsant actions in mouse hippocampal slices, and studied the effects of citalopram on active membrane properties and repetitive action potential firing.

Methods: To enable testing of antiepileptic effects and target modulation in a single experimental system, we used the simplistic low‐Ca2+ model, which is strongly dependent on the intrinsic excitability of CA1 pyramidal neurons. Field potentials and whole‐cell currents were recorded from brain slices, and SSRIs were bath‐applied.

Key Findings: We found that citalopram, fluoxetine, and sertraline inhibited epileptiform activity recorded from area CA1. The effect of citalopram was more potent and less variable than that of fluoxetine and sertraline. The anticonvulsant action of citalopram was accompanied by marked slowing of action potential rise and decay, and robust inhibition of repetitive firing. This depression of membrane excitability appeared to be mediated in part by inhibition of a sustained potassium current.

Significance: These findings confirm that SSRIs can have anticonvulsant effects in the hippocampus, and further suggest that citalopram may exert these effects at least in part by inhibition of voltage‐gated ion currents.