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

Cerebellar neurones show complex and differentiated mechanisms of action potential generationthat have been proposed to depend on peculiarproperties of their voltage-dependent Na+currents. In this study we analysed voltage-dependent Na+currents of rat cerebellar granulecells (GCs) by performing whole-cell, patch-clamp experiments in acute rat cerebellar slices.A transient Na+current (INaT) was always present and had the properties of a typicalfast-activating/inactivating Na+current. In addition toINaT, robust persistent (INaP) andresurgent (INaR)Na+currents were observed.INaPpeaked at∼−40 mV, showed half-maximalactivation at∼−55 mV, and its maximal amplitude was about 1.5% of that ofINaT.INaRwaselicited by repolarizing pulses applied following step depolarizations able to activate/inactivateINaT, and showed voltage- and time-dependent activation and voltage-dependent decay kinetics.The conductance underlyingINaRshowed a bell-shaped voltage dependence, with peak at−35 mV. A significant correlation was found between GCINaRandINaTpeak amplitudes; however,GCs expressingINaTof similar size showed marked variability in terms ofINaRamplitude, andin a fraction of cellsINaRwas undetectable.INaT,INaPandINaRcould be accounted for by a13-state kinetic scheme comprising closed, open,inactivated and blocked states. Current-clampexperiments carried out to identify possible functional correlates ofINaPand/orINaRrevealedthat in GCs single action potentials were followed by depolarizing afterpotentials (DAPs). In amajority of cells, DAPs showed properties consistent withINaRplaying a role in their generation.Computer modelling showed thatINaRpromotes DAP generation and enhances high-frequencyfiring, whereasINaPboosts near-threshold firing activity. Our findings suggest that specialproperties of voltage-dependent Na+currents provides GCs with mechanisms suitable forshaping activity patterns, with potentially important consequences for cerebellar informationtransfer and computation