Contrasting effects of the persistent Na+ current on neuronal excitability and spike timing

The persistent Na+ current, /(NaP), is known to amplify subthreshold oscillations and synaptic potentials, but its impact on action potential generation remains enigmatic. Using computational modeling, whole-cell recording, and dynamic clamp of CA1 hippocampal pyramidal cells in brain slices, we examined how /(NaP) changes the transduction of excitatory current into action potentials. Model simulations predicted that /(NaP) increases afterhyperpolarizations, and, although it increases excitability by reducing rheobase, /(NaP) also reduces the gain in discharge frequency in response to depolarizing current (0 gain). These predictions were experimentally confirmed by using dynamic clamp, thus circumventing the longstanding problem that /(NaP) cannot be selectively blocked. Furthermore, we found that /(NaP) increased firing regularity in response to sustained depolarization, although it decreased spike time precision in response to single evoked EPSPs. Finally, model simulations demonstrated that /(NaP) increased the relative refractory period and decreased interspike-interval variability under conditions resembling an active network in vivo.