Riluzole-sensitive slowly inactivating sodium current in rat suprachiasmatic nucleus neurons

The persistent (i.e., slowly inactivating) fraction of the Na current (I-Na,I-P) regulates excitability of CNS neurons. In isolated rat suprachiasmatic nucleus (SCN) neurons with a ramp-type voltage-clamp protocol, we have studied the properties of a robust current that has the general properties of I-Na,I-P but exhibits a slow inactivation (I-Na,I-S). The time dependence of the development of the inactivation was also studied by clamping of the membrane potential at different levels: time constants ranging from similar to50 to similar to700 ms, depending on the voltage level, were revealed. The I-Na,I-S (50-150 pA) was present in both spontaneously active and silent neurons. The neurons exhibited I-Na,I-S without visible rundown during similar to1-h recordings. I-Na,I-S had a threshold between -65 and -60 mV and was maximal at about -45 mV. Tetrodotoxin (TTX; 1 muM) completely and reversibly blocked I-Na,I-S. Riluzole, an effective blocker of I-Na,I-P, inhibited reversibly I-Na,I-S with an EC50 of 1-2 muM. Microapplication of 10 muM riluzole during either extracellular or intracellular recording suppressed spontaneous activity in isolated SCN neurons. In the slice preparation, bath application of 20 muM riluzole resulted in decreased firing rate or complete suppression of spontaneous activity in some neurons (9/14) but had no effect on other neurons (5/14). In riluzole-resistant neurons in cell-attached experiments, low-amplitude current spikes were present in 1 muM TTX. We concluded that I-Na,I-S is ubiquitously expressed by all SCN neurons and that this current is a necessary but not sufficient depolarizing component of the mechanism for spontaneous firing.