We examined the effects of the Kv4 channel gating modifier NS5806 on somatodendritic A-type channel function and dendritic spread of excitation. We first studied the effects of NS5806 on the currents mediated by Kv4.2 channels coexpressed with different b-subunits in HEK 293 cells, and the effects of NS5806 on the somatodendritic A-type current (I_SA) in hippocampal neurons, using the whole-cell patch-clamp technique. The peak amplitude of currents mediated by ternary Kv4.2 channels, associated with Kv channel interacting protein (KChIP) 3 and dipeptidyl aminopeptidase-related protein (DPP) 6, was potentiated and macroscopic inactivation was slowed by NS5806. The currents mediated by binary Kv4.2 channels, associated only with DPP6, were suppressed by NS5806, and the effects on macroscopic inactivation were less pronounced. The I_SA component in cultured hippocampal neurons was reduced, but showed a pronounced slowing of inactivation in the presence of NS5806. In all cases NS5806 shifted the voltage dependence of steady-state inactivation to more negative potentials. Next we studied the effects of NS5806 on action potential waveform and, with Ca²⁺ imaging techniques, the retrograde spread of excitation in CA1 pyramidal cells of a hippocampal slice preparation. NS5806 reduced upstroke velocity and amplitude of the somatic action potential. Furthermore, NS5806 caused spike broadening and abolished spike after depolarization (ADP). The suppression of back-propagating action potentials (b-APs) was strengthened by NS5806. Our results provide further insights into the molecular and cellular activity of the Kv4 channel gating modifier NS5806.