IONIC MECHANISM OF ELECTRORESPONSIVENESS IN CEREBELLAR GRANULE CELLS IMPLICATES THE ACTION OF A PERSISTENT SODIUM CURRENT

Although substantial knowledge has been accumulated on cerebellar gran ule cell voltage-dependent currents, their role in regulating electror esponsiveness has remained speculative. In this paper, we have used pa tch-clamp recording techniques in acute slice preparations to investig ate the ionic basis of electroresponsiveness of rat cerebellar granule cells at a mature developmental stage. The granule cell generated a N a+ -dependent spike discharge resistant to voltage and time inactivati on, showing a linear frequency increase with injected currents. Action potentials arose when subthreshold depolarizing potentials, which wer e driven by a persistent Na+ current, reached a critical threshold. Th e stability and linearity of the repetitive discharge was based on a c omplex mechanism involving a N-type Ca2+ current blocked by omega-CTx GVIA, and a Ca2+-dependent K+ current blocked by charibdotoxin and low tetraethylammonium (TEA; <1 mM); a voltage-dependent Ca2+-independent K+ current blocked by high TEA (>1 mM); and an A current blocked by 2 mM 4-aminopyridine. Weakening TEA-sensitive K+ currents switched the granule cell into a bursting mode sustained by the persistent Na+ curr ent. A dynamic model is proposed in which the Na+ current-dependent ac tion potential causes secondary Ca2+ current activation and feedback v oltage- and Ca2+ -dependent afterhyperpolarization. The afterhyperpola rization reprimes the channels inactivated in the spike, preventing ad aptation and bursting and controlling the duration of the interspike i nterval and firing frequency. This result reveals complex dynamics beh ind repetitive spike discharge and suggests that a persistent Na+ curr ent plays an important role in action potential initiation and in the regulation of mossy fiber-granule cells transmission.