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bioRxiv · 10.1101/2024.02.15.580453

Ion-channel degeneracy and heterogeneities in the emergence of signature physiological characteristics of dentate gyrus granule cells

Kumari, S.·Narayanan, R.
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Abstract

Complex systems are neither fully determined nor completely random. Biological complex systems, including single neurons, manifest intermediate regimes of randomness that recruit integration of specific combinations of functionally segregated subsystems. Such emergence of biological function provides the substrate for the expression of degeneracy, the ability of disparate combinations of subsystems to yield similar function. Here, we present evidence for the expression of degeneracy in morphologically realistic models of dentate gyrus granule cells (GC) through functional integration of disparate ion-channel combinations. We performed a 45-parameter randomized search spanning 16 active and passive ion channels, each biophysically constrained by their gating kinetics and localization profiles, to search for valid GC models. Valid models were those that satisfied 17 sub- and supra-threshold cellular-scale electrophysiological measurements from rat GCs. A vast majority (>99%) of the 15,000 random models were not electrophysiologically valid, demonstrating that arbitrarily random ion-channel combinations wouldnt yield GC functions. The 141 valid models (0.94% of 15,000) manifested heterogeneities in and cross-dependencies across local and propagating electrophysiological measurements, which matched with their respective biological counterparts. Importantly, these valid models were widespread throughout the parametric space and manifested weak cross-dependencies across different parameters. These observations together showed that GC physiology could neither be obtained by entirely random ion-channel combinations nor is there an entirely determined single parametric combination that satisfied all constraints. The complexity, the heterogeneities in measurement and parametric spaces, and degeneracy associated with GC physiology should be rigorously accounted for, while assessing GCs and their robustness under physiological and pathological conditions. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/580453v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@1fe6e90org.highwire.dtl.DTLVardef@10cc473org.highwire.dtl.DTLVardef@135732dorg.highwire.dtl.DTLVardef@1caec0_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Kumari, S., Narayanan, R.. 2024-02-15. Ion-channel degeneracy and heterogeneities in the emergence of signature physiological characteristics of dentate gyrus granule cells. https://doi.org/10.1101/2024.02.15.580453

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