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

摘要

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_(NaI)) was always present and had the properties of a typical fast-activating/inactivating Na~+ current. In addition to I_(NaI), robust persistent (I_(NaP)) and resurgent (I_(Nar)) Na~+ currents were observed. I_(NaP) peaked at ~ -40 mV, showed half-maximal activation at - - 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_(NaI), 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)x 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) anf 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 after potentials (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.