Kinetic and functional analysis of transient, persistent and resurgent sodium currents in rat cerebellar granule cells in situ: an electrophysiological and modelling study.

ABSTRACT

Cerebellar neurones show complex and differentiated mechanisms of action potential generation that have been proposed to depend on peculiar properties of their voltage-dependent Na+ currents. In this study we analysed voltage-dependent Na(+) currents of rat cerebellar granule cells (GCs) by performing whole-cell, patch-clamp experiments in acute rat cerebellar slices. A transient Na+ current (I(NaT)) was always present and had the properties of a typical fast-activating/inactivating Na+ current. In addition to I(NaT), robust persistent (I(NaP)) and resurgent (I(NaR)) Na+ currents were observed. I(NaP) peaked at approximately -40 mV, showed half-maximal activation at approximately -55 mV, and its maximal amplitude was about 1.5% of that of I(NaT). I(NaR) was elicited by repolarizing pulses applied following step depolarizations able to activate/inactivate I(NaT), and showed voltage- and time-dependent activation and voltage-dependent decay kinetics. The conductance underlying I(NaR) showed a bell-shaped voltage dependence, with peak at -35 mV. A significant correlation was found between GC I(NaR) and I(NaT) peak amplitudes; however, GCs expressing I(NaT) of similar size showed marked variability in terms of I(NaR) amplitude, and in a fraction of cells I(NaR) was undetectable. I(NaT), I(NaP) and I(NaR) could be accounted for by a 13-state kinetic scheme comprising closed, open, inactivated and blocked states. Current-clamp experiments carried out to identify possible functional correlates of I(NaP) and/or I(NaR) revealed that in GCs single action potentials were followed by depolarizing afterpotentials (DAPs). In a majority of cells, DAPs showed properties consistent with I(NaR) playing a role in their generation. Computer modelling showed that I(NaR) promotes DAP generation and enhances high-frequency firing, whereas I(NaP) boosts near-threshold firing activity. Our findings suggest that special properties of voltage-dependent Na+ currents provides GCs with mechanisms suitable for shaping activity patterns, with potentially important consequences for cerebellar information transfer and computation.