Dickson CT, Magistretti J, Shalinsky MH, Fransén E, Hasselmo ME, Alonso A
J. Neurophysiol. 2000 May;83(5):2562-79
Various subsets of brain neurons express a hyperpolarization-activated inward current (I(h)) that has been shown to be instrumental in pacing oscillatory activity at both a single-cell and a network level. A characteristic feature of the stellate cells (SCs) of entorhinal cortex (EC) layer II, those neurons giving rise to the main component of the perforant path input to the hippocampal formation, is their ability to generate persistent, Na(+)-dependent rhythmic subthreshold membrane potential oscillations, which are thought to be instrumental in implementing theta rhythmicity in the entorhinal-hippocampal network. The SCs also display a robust time-dependent inward rectification in the hyperpolarizing direction that may contribute to the generation of these oscillations. We performed whole cell recordings of SCs in in vitro slices to investigate the specific biophysical and pharmacological properties of the current underlying this inward rectification and to clarify its potential role in the genesis of the subthreshold oscillations. In voltage-clamp conditions, hyperpolarizing voltage steps evoked a slow, noninactivating inward current, which also deactivated slowly on depolarization. This current was identified as I(h) because it was resistant to extracellular Ba(2+), sensitive to Cs(+), completely and selectively abolished by ZD7288, and carried by both Na(+) and K(+) ions. I(h) in the SCs had an activation threshold and reversal potential at approximately -45 and -20 mV, respectively. Its half-activation voltage was -77 mV. Importantly, bath perfusion with ZD7288, but not Ba(2+), gradually and completely abolished the subthreshold oscillations, thus directly implicating I(h) in their generation. Using experimentally derived biophysical parameters for I(h) and the low-threshold persistent Na(+) current (I(NaP)) present in the SCs, a simplified model of these neurons was constructed and their subthreshold electroresponsiveness simulated. This indicated that the interplay between I(NaP) and I(h) can sustain persistent subthreshold oscillations in SCs. I(NaP) and I(h) operate in a “push-pull” fashion where the delay in the activation/deactivation of I(h) gives rise to the oscillatory process.