Ion-channel regulation of response decorrelation in a heterogeneous multi-scale model of the dentate gyrus

Abstract

Heterogeneities in biological neural circuits manifest in afferent connectivity as well as in local-circuit components such as neuronal excitability, neural structure and local synaptic strengths. The expression of adult neurogenesis in the dentate gyrus (DG) amplifies local-circuit heterogeneities and guides heterogeneities in afferent connectivity. How do neurons and their networks endowed with these distinct forms of heterogeneities respond to perturbations to individual ion channels, which are known to change under several physiological and pathophysiological conditions? We sequentially traversed the ion channels-neurons-network scales and assessed the impact of eliminating individual ion channels on conductance-based neuronal and network models endowed with disparate local-circuit and afferent heterogeneities. We found that many ion channels differentially contributed to specific neuronal or network measurements, and the elimination of any given ion channel altered several functional measurements. We then quantified the impact of ion-channel elimination on response decorrelation, a well-established metric to assess the ability of neurons in a network to convey complementary information, in DG networks endowed with different forms of heterogeneities. Notably, we found that networks constructed with structurally immature neurons exhibited functional robustness, manifesting as minimal changes in response decorrelation in the face of ion-channel elimination. Importantly, the average change in output correlation was dependent on the eliminated ion channel but invariant to input correlation. Our analyses suggest that neurogenesis-driven structural heterogeneities could assist the DG network in providing functional resilience to molecular perturbations.

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

“…Although our study focused on four subtypes of ion channels, future studies could extend such analyses to other ion channels, including calcium‐activated potassium channels, voltage‐gated calcium channels, and other sodium and potassium channels in DG granule cells. Based on earlier computational predictions in DG granule cells (Beining et al, 2017 ; Mishra & Narayanan, 2019 , 2021 ), and on electrophysiological observations here, we postulate that the incorporation of additional channels to the analyses would further increase the degrees of freedom available to the neuron in maintaining similar function.…”

“…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 ): Knocking out or perturbing any single ion channel altered multiple cellular‐scale physiological measurements, and any specific cellular‐scale physiological measurement was altered by knocking out or perturbing several ion channels; and The impact of blocking individual ion channels on cellular‐scale measurements is variable. Specifically, the expression of ion‐channel degeneracy translates to differential expression of individual ion‐channels in different neurons of the same subtype.…”

“…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 DG granule neurons, which has been predicted by computational studies (Beining et al, 2017 ; Mishra & Narayanan, 2019 , 2021 ). Specifically, 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 also result in heterogeneous impact on the same measurement in different cells.…”

“…The construction of such models could involve independent multi‐parametric multi‐objective stochastic search (MPMOSS) algorithms (Basak & Narayanan, 2018 ; Foster et al, 1993 ; Jain & Narayanan, 2020 ; Marder & Taylor, 2011 ; Mishra & Narayanan, 2019 ; Mittal & Narayanan, 2018 ; Rathour & Narayanan, 2012a , 2014 ; Seenivasan & Narayanan, 2020 ; Taylor et al, 2009 ) for each of the different subregions and sectors. Such analyses could involve the virtual knockout model strategy where all measurements are repeated across the population of models with each of the several ion channels individually eliminated (Anirudhan & Narayanan, 2015 ; Basak & Narayanan, 2018 , 2020 ; Jain & Narayanan, 2020 ; Mishra & Narayanan, 2021 ; Mukunda & Narayanan, 2017 ; Rathour & Narayanan, 2014 ; Sinha & Narayanan, 2015 ). These approaches could be repeated for adult‐born neurons of different age groups across different subregions, thus extending the analyses to structural heterogeneities as well.…”

“…In earlier studies (Mishra & Narayanan, 2019 , 2021 ), we had employed computational models to hypothesize the expression of ion‐channel degeneracy in the emergence of cellular‐scale function in the granule cells of the dentate gyrus (DG), with additional support from other computational studies on these cell types (Beining et al, 2017 ). In this study, we aimed to experimentally test this hypothesis by recording several cellular‐scale physiological measurements from DG granule cells using whole‐cell patch‐clamp electrophysiology, before and after treatment with distinct pharmacological agents that block four different subtypes of non‐inactivating subthreshold‐activated ion channels.…”