Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin gene family, is an important signaling molecule that plays a crucial role as mediator of synaptic and morphological plasticity in the central nervous system. Recently, we described that BDNF, but not proBDNF, within minutes decreases the excitability of fast-spiking interneurons in the dentate gyrus (Holm et al., 2009). Aim: Here, our aim was to identify ion channels participating in the immediate effect of BDNF on the excitability of fast-spiking interneurons. Methods: Whole-cell recordings were obtained from interneurons in P14- 18 rat brain slices. Results: In current-clamp recording , BDNF (15 ng/ml) decreased the action potential frequency (control 7.5 ± 1.4 Hz, BDNF 1.4 ± 0.4 Hz, P<0.05) evoked by depolarizing steps (500 ms, 1 Hz). Next, we recorded the firing frequency in the presence of intracellular BAPTA (10 mM). The afterhyperpolarization phase was reduced compared with control, but BAPTA did not alter the effect of BDNF on firing frequency (control 6.5 ± 1.5 Hz, BDNF 1.5 ± 0.4 Hz, P<0.05), suggesting that the BDNF effect is not mediated by calcium signaling. In contrast, BDNF effects on firing frequency were fully abolished after application of BDNF in presence of the potassium channel blockers TEA (20 mM) or 4-AP (1 mM). Similarly, XE-991 (8 mM), a specific blocker of Kv7/KNCQ/M channels, abolished the effect of BDNF. In agreement, application of retigabine (10 mM), an opener of Kv7/KNCQ/M channels, mimicked the effect of BDNF on firing frequency (control 8.8 ± 0.9 Hz, Retigabine 0.8 ± 0.6 Hz, P<0.05). Conclusion: In conclusion, BDNF depresses the excitability of fast-spiking interneurons through activation of an M-like potassium current.