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Correspondence to: Angel Alonso, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, Montréal, Québec, H3A 2B4 Canada. Fax: (514) 398-8106; E-mail:mdao{at}musica.mcgill.ca.
The functional and biophysical properties of a sustained, or "persistent," Na+ current (INaP) responsible for the generation of subthreshold oscillatory activity in entorhinal cortex layer-II principal neurons (the "stellate cells") were investigated with whole-cell, patch-clamp experiments. Both acutely dissociated cells and slices derived from adult rat entorhinal cortex were used. INaP , activated by either slow voltage ramps or long-lasting depolarizing pulses, was prominent in both isolated and, especially, in situ neurons. The analysis of the gating properties of the transient Na+ current (INaT) in the same neurons revealed that the resulting time-independent "window" current (INaTW) had both amplitude and voltage dependence not compatible with those of the observed INaP , thus implying the existence of an alternative mechanism of persistent Na+-current generation. The tetrodotoxin-sensitive Na+ currents evoked by slow voltage ramps decreased in amplitude with decreasing ramp slopes, thus suggesting that a time-dependent inactivation was taking place during ramp depolarizations. When ramps were preceded by increasingly positive, long-lasting voltage prepulses, INaP was progressively, and eventually completely, inactivated. The V1/2 of INaP steady state inactivation was approximately -49 mV. The time dependence of the development of the inactivation was also studied by varying the duration of the inactivating prepulse: time constants ranging from ~6.8 to ~2.6 s, depending on the voltage level, were revealed. Moreover, the activation and inactivation properties of INaP were such as to generate, within a relatively broad membrane-voltage range, a really persistent window current (INaPW). Significantly, INaPW was maximal at about the same voltage level at which subthreshold oscillations are expressed by the stellate cells. Indeed, at -50 mV, the INaPW was shown to contribute to >80% of the persistent Na+ current that sustains the subthreshold oscillations, whereas only the remaining part can be attributed to a classical Hodgkin-Huxley INaTW. Finally, the single-channel bases of INaP slow inactivation and INaPW generation were investigated in cell-attached experiments. Both phenomena were found to be underlain by repetitive, relatively prolonged late channel openings that appeared to undergo inactivation in a nearly irreversible manner at high depolarization levels (-10 mV), but not at more negative potentials (-40 mV).
Key Words: persistent Na+ current, window current, stellate cells, oscillations, patch clamp
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