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Original Article

A Whole-Cell and Single-Channel Study

Jacopo Magistretti^a,b and Angel Alonso^a

^a From the Department of Neurology and Neurosurgery, McGill University and Montreal Neurological Institute, Montréal, Québec, H3A 2B4 Canada
^b Dipartimento di Neurofisiologia Sperimentale, Istituto Nazionale Neurologico "Carlo Besta", 20133 Milano, Italy
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, Montréal, Québec, H3A 2B4 Canada.Fax: (514) 398-8106;

mdao{at}musica.mcgill.ca

The functional and biophysical properties of a sustained, or "persistent," Na⁺ current (I_NaP) 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. I_NaP , 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 (I_NaT) in the same neurons revealed that the resulting time-independent "window" current (I_NaTW) had both amplitude and voltage dependence not compatible with those of the observed I_NaP , 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, I_NaP was progressively, and eventually completely, inactivated. The V_1/2 of I_NaP 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 I_NaP were such as to generate, within a relatively broad membrane-voltage range, a really persistent window current (I_NaPW). Significantly, I_NaPW was maximal at about the same voltage level at which subthreshold oscillations are expressed by the stellate cells. Indeed, at –50 mV, the I_NaPW 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 I_NaTW. Finally, the single-channel bases of I_NaP slow inactivation and I_NaPW 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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