Ionic mechanism of electroresponsiveness in cerebellar granule cells implicates the action of a persistent sodium current.
Although substantial knowledge has been accumulated on cerebellar granule cell voltage-dependent currents, their role in regulating electroresponsiveness has remained speculative. In this paper, we have used patch-clamp recording techniques in acute slice preparations to investigate the ionic basis of electroresponsiveness of rat cerebellar granule cells at a mature developmental stage. The granule cell generated a Na+-dependent spike discharge resistant to voltage and time inactivation, showing a linear frequency increase with injected currents. Action potentials arose when subthreshold depolarizing potentials, which were driven by a persistent Na+ current, reached a critical threshold. The stability and linearity of the repetitive discharge was based on a complex 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+ current. A dynamic model is proposed in which the Na+ current-dependent action potential causes secondary Ca2+ current activation and feedback voltage- and Ca2+-dependent afterhyperpolarization. The afterhyperpolarization reprimes the channels inactivated in the spike, preventing adaptation and bursting and controlling the duration of the interspike interval and firing frequency. This result reveals complex dynamics behind repetitive spike discharge and suggests that a persistent Na+ current plays an important role in action potential initiation and in the regulation of mossy fiber-granule cells transmission.
D'Angelo
E
E
Istituto di Fisiologia Generale and Istituto Nazionale per la Fisice della Meterie, Pavia Unit, I-27100 Pavia, Italy.
De Filippi
G
G
Rossi
P
P
Taglietti
V
V
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology; D002531:Cerebellum / Q000166:cytology*; D018999:Charybdotoxin / Q000494:pharmacology; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D009412:Nerve Fibers / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D010507:Periodicity; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology; D019789:Tetraethylammonium / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D020866:omega-Conotoxin GVIA
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018691:Excitatory Amino Acid Antagonists; D010455:Peptides; D015221:Potassium Channels; D015222:Sodium Channels; D018999:Charybdotoxin; D013779:Tetrodotoxin; D019789:Tetraethylammonium; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; D020866:omega-Conotoxin GVIA; D012964:Sodium; D011188:Potassium; D002118:Calcium