Properties and Role of I _h in the Pacing of Subthreshold Oscillations in Entorhinal Cortex Layer II Neurons

Abstract

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 Ba2+, 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 Ba2+, 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.

Differential contribution of kainate receptors to excitatory postsynaptic currents in superficial layer neurons of the rat medial entorhinal cortex

“…We refer to these neuronal classes as Sag (S), Intermediate Sag (IS), and No Sag (NS) neurons. This sag potential has been attributed to the presence of I h in these neurons (Dickson et al, 2000b). Biocytin labeling of recorded neurons revealed that NS neurons were localized to Layer III and exhibited pyramidal-like morphology.…”

The role of ongoing dendritic oscillations in single-neuron dynamics

“…Finally, we determine the phase-locking under both passive and active cable coupling for a model of subthreshold oscillations in entorhinal stellate cells [6,13]. These oscillations are thought to arise from an interaction between a persistent sodium current I NaP and a hyperpolarization-activated inward current I h (see Methods).…”

“…The oscillatory dynamics emerge from the interaction between the persistent sodium current I NaP and the hyperpolarization activated inward current I h . The current descriptions are based on the data from [13,14]. The dynamics of I h are described by a single gating variable w(t) with activation function w ∞ (V ) and time constant τ w (V )/ϕ (in milliseconds).…”

“…Several ionic conductances can underlie these oscillations. In entorhinal cortex stellate cells, experiments have shown that the oscillations result from an interaction of the persistent sodium current I NaP and the hyperpolarization activated inward current I h [6,13,14]. Recordings from hippocampal CA1 pyramidal neurons have also demonstrated ongoing oscillations in the dendrites that include repetitive dendritic spikes, presumably involving Ca 2+ currents [15].…”

Grid cell mechanisms and function: Contributions of entorhinal persistent spiking and phase resetting

“…Previous modeling showed how these differences in membrane potential oscillation frequency could underlie differences in grid cell spatial periodicity along the dorsal to ventral axis Giocomo et al, 2007;Hasselmo et al, 2007;Giocomo and Hasselmo, 2008a). The oscillations appear to be due to a hyperpolarization-activated cation current known as the h-current (Dickson et al, 2000) that differs in time constant along the dorsal to ventral axis (Giocomo and Hasselmo, 2008b). In contrast to stellate cells, membrane potential oscillations do not usually appear in Layer II and III pyramidal cells (Alonso and Klink, 1993), but are observed in Layer V pyramidal cells, where they may be caused by M-current (Yoshida and Alonso, 2007;Giocomo and Hasselmo, 2008a).…”