Resurgent Na Currents in Four Classes of Neurons of the Cerebellum

Abstract

Action potential firing rates are generally limited by the refractory period, which depends on the recovery from inactivation of voltage-gated Na channels. In cerebellar Purkinje neurons, the kinetics of Na channels appear specialized for rapid firing. Upon depolarization, an endogenous open-channel blocker rapidly terminates current flow but prevents binding of the “fast” inactivation gate. Upon repolarization, unbinding of the blocker produces “resurgent” Na current while allowing channels to recover rapidly. Because other cerebellar neurons, including granule cells, unipolar brush cells, and neurons of the cerebellar nuclei, also fire rapidly, we tested whether these cells might also express Na channels with resurgent kinetics. Neurons were acutely isolated from mice and rats, and TTX-sensitive Na currents were recorded under voltage clamp. Unlike Purkinje cells, the other cerebellar neurons produced only tiny resurgent currents in solutions optimized for voltage-clamping Na currents (50 mM Na+; Co2+ substitution for Ca2+). Under more physiological ionic conditions (155 mM Na+; 2 mM Ca2+ with 0.03 mM Cd2+), however, granule cells, unipolar brush cells, and cerebellar nuclear cells all produced robust resurgent currents. The increase in resurgent current, which was greater than predicted by the Goldman-Hodgkin-Katz equation, appeared to result from a combination of knock-off of open-channel blockers by permeating ions as well as relief of divalent block at negative potentials. These results indicate that resurgent current is typical of many cerebellar neurons and suggest that rapid open-channel block and unblock may be a widespread mechanism for restoration of Na channel availability in rapidly firing neurons.

Functional reciprocity between Na + channel Na v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

“…This resurgent I Na is proposed to promote repetitive firing by rapidly restoring VGSC availability (32). We found that resurgent I Na was reduced in 14 DIV Scn1b null CGNs (P = 0.01; Fig.…”

Sodium Currents in Medullary Neurons Isolated from the Pre-Bötzinger Complex Region

“…3 E, F ) (see below). In contrast, use of a lowered external sodium concentration (15 mM in the current study) to improve the space clamp may have reduced the slope factor, as has been found for cerebellar neurons (Afshari et al, 2004). Additionally, the shallow slope is consistent with the presence of multiple sodium channels with slight differences in the voltage dependence of inactivation, thereby extending the voltage range over which inactivation occurred.…”

Reduced Sodium Current in Purkinje Neurons from NaV1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy

“…The extracellular solution contained the following: 20 mM NaCl, 10 mM HEPES, 2 mM BaCl 2 , 300 M CdCl 2 , 140 mM tetraethylammonium-Cl, at pH 7.4. This low (20 mM) sodium concentration was used to improve control of the cell membrane voltage during voltage-clamp experiments on Purkinje neurons, which produce large sodium currents (Afshari et al, 2004). For recording resurgent currents, sodium concentration in the extracellular solution was raised to 50 mM to produce larger currents that could be analyzed more accurately and tetraethylammonium-Cl was reduced to 110 mM.…”

“…Resurgent sodium current, a component of sodium current that flows transiently on repolarization of the cell, has been identified in cerebellar Purkinje neurons and other central neurons (Raman and Bean, 1997; Afshari et al, 2004;Do and Bean, 2004). Like the persistent sodium current, resurgent current has been implicated in promoting fast repetitive neuronal firing in these neurons Bean, 1997, 1999a; by accelerating depolarization toward threshold between action potentials (Raman and Bean, 1999a).…”