HCN1 Channels Control Resting and Active Integrative Properties of Stellate Cells from Layer II of the Entorhinal Cortex

Abstract

Whereas recent studies have elucidated principles for representation of information within the entorhinal cortex, less is known about the molecular basis for information processing by entorhinal neurons. The HCN1 gene encodes ion channels that mediate hyperpolarizationactivated currents (I h ) that control synaptic integration and influence several forms of learning and memory. We asked whether hyperpolarization-activated, cation nonselective 1 (HCN1) channels control processing of information by stellate cells found within layer II of the entorhinal cortex. Axonal projections from these neurons form a major component of the synaptic input to the dentate gyrus of the hippocampus. To determine whether HCN1 channels control either the resting or the active properties of stellate neurons, we performed whole-cell recordings in horizontal brain slices prepared from adult wild-type and HCN1 knock-out mice. We found that HCN1 channels are required for rapid and full activation of hyperpolarization-activated currents in stellate neurons. HCN1 channels dominate the membrane conductance at rest, are not required for theta frequency (4 -12 Hz) membrane potential fluctuations, but suppress low-frequency (Ͻ4 Hz) components of spontaneous and evoked membrane potential activity. During sustained activation of stellate cells sufficient for firing of repeated action potentials, HCN1 channels control the pattern of spike output by promoting recovery of the spike afterhyperpolarization. These data suggest that HCN1 channels expressed by stellate neurons in layer II of the entorhinal cortex are key molecular components in the processing of inputs to the hippocampal dentate gyrus, with distinct integrative roles during resting and active states.

The Range of Intrinsic Frequencies Represented by Medial Entorhinal Cortex Stellate Cells Extends with Age

“…Consequently, the range of resonance frequencies recorded by sharp microelectrodes was larger (the cutoff frequency of the cell low-pass filter depends on 1/2 m ). In both age groups, the resonance frequency decreased on depolarization similar as reported by Nolan et al (2007), although the effect was weak when measured by sharp microelectrodes, similar to the study by Erchova et al (2004). In all cases, the resonance frequency measured near threshold was larger than the frequency of MPOs, as we previously reported Engel et al, 2008).…”

Artificial Synaptic Conductances Reduce Subthreshold Oscillations and Periodic Firing in Stellate Cells of the Entorhinal Cortex

“…Hence, the peak in the PSD could result from an increased probability of firing after a spike AHP, and not directly from subthreshold oscillatory behavior. In fact, previous modeling and experimental data in stellate cells suggests that the dynamics underlying the AHP are important in the formation of spike clusters (Fransen et al, 2004;Nolan et al, 2007). We hypothesized that changes in membrane conductance and time constant could potentially alter the AHP shape and rebound behavior in stellate cells, and thus alter the expression of theta oscillations in the spike train To quantify the changes in the AHP of stellate cells, we averaged the membrane potential after the peak of the spike for a duration 0.3 s. Because of small variations in spike threshold between cells, spikes were lined up at the voltage threshold for comparison.…”

Computation by oscillations: Implications of experimental data for theoretical models of grid cells

“…In stellate cells, the kinetics of the h-current resemble those of heteromultimeric HCN1/HCN2 channels (Chen et al, 2001). Research in HCN1 knockout mice suggests that HCN1 channels, in stellate cells, dominate the membrane conductance at resting potential, decrease the input resistance of the cell, suppress low frequency components of the resonant frequency and subthreshold oscillations, and promote recovery of spike after hyperpolarization (Nolan et al, 2007). In addition, stellate cells often fire action potentials in clusters (Klink and Alonso, 1997b), and knockout of HCN1 decreases the spike frequency within a cluster and increases the time between clusters (the intracluster spike frequency) (Nolan et al, 2007).…”

“…Research in HCN1 knockout mice suggests that HCN1 channels, in stellate cells, dominate the membrane conductance at resting potential, decrease the input resistance of the cell, suppress low frequency components of the resonant frequency and subthreshold oscillations, and promote recovery of spike after hyperpolarization (Nolan et al, 2007). In addition, stellate cells often fire action potentials in clusters (Klink and Alonso, 1997b), and knockout of HCN1 decreases the spike frequency within a cluster and increases the time between clusters (the intracluster spike frequency) (Nolan et al, 2007). HCN1 knockout mice also show more coherence in the theta oscillation, recorded from behaving mice, suggesting that knocking down high frequency intrinsic oscillations may result in a more coherent field oscillation in the theta frequency range (Nolan et al, 2004).…”