Ion Channel Degeneracy, Variability, and Covariation in Neuron and Circuit Resilience

Abstract

The large number of ion channels found in all nervous systems poses fundamental questions concerning how the characteristic intrinsic properties of single neurons are determined by the specific subsets of channels they express. All neurons display many different ion channels with overlapping voltage- and time-dependent properties. We speculate that these overlapping properties promote resilience in neuronal function. Individual neurons of the same cell type show variability in ion channel conductance densities even though they can generate reliable and similar behavior. This complicates a simple assignment of function to any conductance and is associated with variable responses of neurons of the same cell type to perturbations, deletions, and pharmacological manipulation. Ion channel genes often show strong positively correlated expression, which may result from the molecular and developmental rules that determine which ion channels are expressed in a given cell type. Expected final online publication date for the Annual Review of Neuroscience, Volume 44 is July 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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

“…Together, our results emphasize ion‐channel degeneracy and the associated heterogeneous impact of different ion channel subtypes on neuronal functions to constitute defining characteristics of neuronal physiology. Our results demonstrate the impact of multiple ion channels on the same set of physiological measurements, and emphasize the need to account for ion‐channel degeneracy in interpreting physiological experiments and in understanding the etiology of or designing remedies for pathological conditions (Edelman & Gally, 2001 ; Goaillard & Marder, 2021 ; Goaillard et al, 2009 ; Leonardo, 2005 ; Marder, 2011 ; Marder & Goaillard, 2006 ; Marder & Taylor, 2011 ; Price & Friston, 2002 ; Rathour & Narayanan, 2019 ; Ratté et al, 2014 ).…”

“…This form of degeneracy points to the emergence of similar cellular‐scale function (signature neuronal intrinsic properties) through disparate combinations of structural components in the molecular scale (different ion channel subtypes). The ability of disparate ion‐channel combinations to elicit cell type‐specific characteristic cellular‐scale physiological signatures (including intrinsic excitability) provides an advantage by tremendously increasing the degrees of freedom available to a neuron to achieve robustness in functionality (Goaillard & Marder, 2021 ). Such ion‐channel degeneracy also provides a clear explanation for why different neurons with similar signature cellular‐scale function exhibit widespread heterogeneity in their ion‐channel composition, as this would be a direct consequence of different sets of ion channels mediating cellular functions in different neurons (Goaillard & Marder, 2021 ; Goaillard et al, 2009 ; Golowasch et al, 1992 ; Ma & Koester, 1996 ; Rathour et al, 2016 ; Swensen & Bean, 2003 , 2005 ).…”

“…An elegant answer to this question arises from the degeneracy framework (Edelman & Gally, 2001 ), which postulates that disparate structural combinations could elicit similar function. With reference to the specific question on neuronal intrinsic characteristics, computational studies have pointed to the expression of degeneracy in terms of disparate ion channel combinations yielding characteristic cellular‐scale physiological signatures in different cell types, a phenomenon that has been referred to as ion‐channel degeneracy (Achard & De Schutter, 2006 ; Alonso & Marder, 2019 ; Das et al, 2017 ; Drion et al, 2015 ; Gjorgjieva et al, 2016 ; Goaillard & Marder, 2021 ; Gunay et al, 2008 ; Marder, 2011 ; Marder & Goaillard, 2006 ; Migliore et al, 2018 ; Mishra & Narayanan, 2019 ; Mittal & Narayanan, 2018 ; O'Leary, 2018 ; Onasch & Gjorgjieva, 2020 ; Rathour & Narayanan, 2012a , 2014 , 2019 ; Taylor et al, 2009 ). In this study, employing dentate gyrus granule cells as the substrate, we electrophysiologically tested the expression of ion‐channel degeneracy in the emergence of cellular‐scale physiology.…”

Dominant role of adult neurogenesis-induced structural heterogeneities in driving plasticity heterogeneity in dentate gyrus granule cells

“…The predominant implication for the expression of degeneracy in the concomitant emergence of intrinsic properties and plasticity profiles is the explosion in the degrees of freedom available for the neurons to achieve these characteristic features, thereby providing multiple routes to achieving functional robustness (Edelman and Gally, 2001; Rathour and Narayanan, 2019; Goaillard and Marder, 2021). In addition, given the expression of such degeneracy, it is essential that the theoretical and experimental analyses recognize that the mappings between structural components and functional outcomes are many-to-many, and avoid reductionist oversimplifications of structure-function relationships (Rathour and Narayanan, 2019; Goaillard and Marder, 2021; Mishra and Narayanan, 2021a, c). An essential first step in achieving this is the quantification of heterogeneities in the dependencies of each of the several functional outcomes on the individual structural components (Mishra and Narayanan, 2021a, c) — with examples including the different ion-channel/receptor subtypes and the distinct calcium handling mechanisms.…”

“…The validation process resulted in 126 valid models that manifested characteristic electrophysiological properties of granule cells, but exhibited pronounced heterogeneities in channel composition and other biophysical parameters (Mishra and Narayanan, 2019). This constitutes an instance of ion-channel degeneracy (Mishra and Narayanan, 2019; Rathour and Narayanan, 2019; Goaillard and Marder, 2021; Mishra and Narayanan, 2021a) in the emergence of cellular-scale properties, and provided 126 GC models that were endowed with signature heterogeneities in their intrinsic properties. In our analyses, this population of 126 GC models from (Mishra and Narayanan, 2019) was employed as the substrate for assessing the impact of intrinsic heterogeneities on synaptic plasticity profiles.…”