Ion‐channel degeneracy: Multiple ion channels heterogeneously regulate intrinsic physiology of rat hippocampal granule cells

Abstract

Degeneracy, the ability of multiple structural components to elicit the same characteristic functional properties, constitutes an elegant mechanism for achieving biological robustness. In this study, we sought electrophysiological signatures for the expression of ion‐channel degeneracy in the emergence of intrinsic properties of rat hippocampal granule cells. We measured the impact of four different ion‐channel subtypes—hyperpolarization‐activated cyclic‐nucleotide‐gated (HCN), barium‐sensitive inward rectifier potassium (K ir ), tertiapin‐Q‐sensitive inward rectifier potassium, and persistent sodium (NaP) channels—on 21 functional measurements employing pharmacological agents, and report electrophysiological data on two characteristic signatures for the expression of ion‐channel degeneracy in granule cells. First, the blockade of a specific ion‐channel subtype altered several, but not all, functional measurements. Furthermore, any given functional measurement was altered by the blockade of many, but not all, ion‐channel subtypes. Second, the impact of blocking each ion‐channel subtype manifested neuron‐to‐neuron variability in the quantum of changes in the electrophysiological measurements. Specifically, we found that blocking HCN or Ba‐sensitive K ir channels enhanced action potential firing rate, but blockade of NaP channels reduced firing rate of granule cells. Subthreshold measures of granule cell intrinsic excitability (input resistance, temporal summation, and impedance amplitude) were enhanced by blockade of HCN or Ba‐sensitive K ir channels, but were not significantly altered by NaP channel blockade. We confirmed that the HCN and Ba‐sensitive K ir channels independently altered sub‐ and suprathreshold properties of granule cells through sequential application of pharmacological agents that blocked these channels. Finally, we found that none of the sub‐ or suprathreshold measurements of granule cells were significantly altered upon treatment with tertiapin‐Q. Together, the heterogeneous many‐to‐many mapping between ion channels and single‐neuron intrinsic properties emphasizes the need to account for ion‐channel degeneracy in cellular‐ and network‐scale physiology.

Conjunctive changes in multiple ion channels mediate activity-dependent intrinsic plasticity in hippocampal granule cells

“…These changes are broadly consistent with an increased current passage through HCN channels, which are hyperpolarization-activated channels that mediate an inward current that is active under resting conditions. Specifically, it has been shown that increases in HCN channels and the associated h current result in depolarization of RMP, a reduction of R in , |Z| max and S a (Magee, 1998;Narayanan and Johnston, 2007;Mishra and Narayanan, 2021a;Stegen et al, 2012). We asked if other TBF-induced sub-threshold changes were also consistent with changes in HCN channels.…”

“…Synergistic interactions between HCN and inward-rectifier potassium channels mediate TBF-induced reduction in sub-threshold excitability of DG granule cells ZD7288, an HCN-channel blocker, significantly reduces sub-and supra-threshold excitability of DG granule cells (Mishra and Narayanan, 2021a). Encouraged by these strong physiological lines of evidence on the potential role of resting conductances in sub-threshold plasticity (Figure 4C-4F), we first tested the time-dependent effect of ZD7288 on the intrinsic properties of DG granule cells.…”

“…As inward rectifier potassium (K ir ) channels, which mediate another resting conductance, are known regulators of granule cell excitability (Mishra and Narayanan, 2021a;Stegen et al, 2009Stegen et al, , 2012Young et al, 2009), we pharmacologically assessed their role in TBF-induced plasticity using 50-mM BaCl 2 , a blocker 6E), there were significant increases in firing rate over the period (Figure 6F; BaCl 2 Control). With TBF experiments, we found that the presence of BaCl 2 blocked TBF-induced reduction in R in and other sub-threshold measurements (Figure 6).…”

“…Our observations on TBF-induced enhancement in supra-threshold excitability pointed to changes in a regenerative conductance. Motivated by the expression of a persistent sodium (NaP) channel in DG granule cells predominantly in the axonal initial segment, and the role of these channels in regulating AP firing properties (Artinian et al, 2011;Crill, 1996;Ellerkmann et al, 2003;Epsztein et al, 2010;Kress et al, 2010;Mishra and Narayanan, 2021a), we assessed TBF-induced plasticity in the presence of riluzole, a blocker of NaP channels (Song et al, 1997;Urbani and Belluzzi, 2000). We observed a significant reduction in R in (Figures 7A-7C; Riluzole Control), but not |Z| max (Figures 7D-7F; Riluzole Control) over a 45-min period long-term control, even when we pre-treated the slice with riluzole before beginning our recordings.…”

“…Such activation of two-pore domain potassium channels could potentially explain the time dependent reduction in R in we observed. In addition, there are known nonspecificities of ZD7288 (Chen, 2004;Chevaleyre and Castillo, 2002;Sanchez-Alonso et al, 2008), Ba 2+ (Zhou et al, 2012), which constitute well-established limitations of the use of pharmacological agents (discussed in the context of DG granule cells in (Mishra and Narayanan, 2021a)). However, in our study, we have also employed a constellation of physiological measurements showing signature physiological changes (Figures 1, 2, 3, and 4) to provide lines of evidence for roles of the different ion channels in the reported form of plasticity.…”