Abstract
channels are uniquely positioned to act as neuromodulatory control points for tuning hippocampal theta (4–12 Hz) and gamma (25 Hz) oscillations, oscillations which are thought to have importance for organization of information flow. contributes to neuronal membrane resonance and resting membrane potential, and is modulated by second messengers. We investigated oscillatory control using a multiscale computer model of hippocampal CA3, where each cell class (pyramidal, basket, and oriens-lacunosum moleculare cells), contained type-appropriate isoforms of . Our model demonstrated that modulation of pyramidal and basket allows tuning theta and gamma oscillation frequency and amplitude. Pyramidal also controlled cross-frequency coupling (CFC) and allowed shifting gamma generation towards particular phases of the theta cycle, effected via 's ability to set pyramidal excitability. Our model predicts that in vivo neuromodulatory control of allows flexibly controlling CFC and the timing of gamma discharges at particular theta phases.
Highlights
The hyperpolarization-activated cyclic-nucleotide gated (HCN) channel is a voltage-gated ion channel involved in sub-threshold resonance [1,2,3,4]
Ih is uniquely positioned for these roles for several reasons: 1) Ih enhances resonance in individual neurons, 2) Ih contributes to resting membrane potential, and neuronal excitability, 3) multiple HCN isoforms are differentially expressed in different cell types known to contribute to different oscillation frequencies, and 4) neuromodulators allow precise control of the conductance of specific HCN isoforms via second-messenger signaling cascades [7,43]
These functions of theta and gamma oscillations are linked to different aspects of cognition and behavior: cross-frequency coupling (CFC) level is correlated with hippocampal-dependent learning performance [21,45] and attentional modulation [46], Figure 5
Summary
The hyperpolarization-activated cyclic-nucleotide gated (HCN) channel is a voltage-gated ion channel involved in sub-threshold resonance [1,2,3,4]. Ih is peculiar/ funny/queer/anomalous because, unlike most channels, it inactivates with depolarization (hyperpolarization-activated). Another peculiarity is its mixed permeability, which gives it an intermediate reversal potential (Erev) near 230 mV, unlike many channels which are dominated by a major permeability to Naz, Kz, or Cazz. We placed slow excitatory inputs in the last distal apical compartment of pyramidal cells, in order to model input from the entorhinal cortex. This input was capable of simulating calcium-spike-like activity in the dendritic compartment and driving sparse firing of pyramidal cells.
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