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 (Kir), 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 Kir 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 Kir channels, but were not significantly altered by NaP channel blockade. We confirmed that the HCN and Ba‐sensitive Kir 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.
Highlights
Robust maintenance of neuronal intrinsic excitability and associated electrophysiological characteristics is critical to neuronal and network physiology, as perturbations to these properties result in pathological conditions (Beck & Yaari, 2008; Kullmann & Waxman, 2010; Marder & Goaillard, 2006; Nelson & Turrigiano, 2008; O'Leary, 2018; Poolos & Johnston, 2012; Rathour & Narayanan, 2019; Terzic & Perez- Terzic, 2010; Turrigiano, 2011)
The principal goal of our study was to seek electrophysiological evidence for two signature characteristics that point to the expression of ion-channel degeneracy in the emergence of single-neuron physiology of dentate gyrus (DG) granule neurons, which has been predicted by computational studies (Beining et al, 2017; Mishra & Narayanan, 2019, 2021)
We reasoned that the expression of ion-channel degeneracy would translate to the ability of multiple ion channels to alter the same functional measurement and would result in heterogeneous impact on the same measurement in different cells
Summary
Robust maintenance of neuronal intrinsic excitability and associated electrophysiological characteristics is critical to neuronal and network physiology, as perturbations to these properties result in pathological conditions (Beck & Yaari, 2008; Kullmann & Waxman, 2010; Marder & Goaillard, 2006; Nelson & Turrigiano, 2008; O'Leary, 2018; Poolos & Johnston, 2012; Rathour & Narayanan, 2019; Terzic & Perez- Terzic, 2010; Turrigiano, 2011). This implies that, in systems expressing degeneracy, perturbation of any single structural component would elicit variable impact on functional outcomes Consistent with this general framework, prior computational studies, involving ion-channel knockouts or perturbations, have revealed important testable predictions that point to the expression of ion-channel degeneracy in the emergence of cellular-scale function (Basak & Narayanan, 2018, 2020; Beining et al, 2017; Drion et al, 2015; Jain & Narayanan, 2020; Marder, 2011; Marder & Goaillard, 2006; Mishra & Narayanan, 2019, 2021; Mittal & Narayanan, 2018; O'Leary, 2018; Onasch & Gjorgjieva, 2020; Rathour & Narayanan, 2014): 1. We aimed to experimentally test this hypothesis by recording several cellular-scale physiological measurements from DG granule cells using whole-c ell patch-clamp electrophysiology, before and after treatment with distinct pharmacological agents that block four different subtypes of non-inactivating subthreshold-activated ion channels. Our results provide experimental evidence for a heterogeneous many-to-many mapping between ion channels and single-neuron intrinsic properties, thereby electrophysiologically testing the postulate on the expression of ion-channel degeneracy in DG granule cells
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