Minimal requirements for a neuron to coregulate many properties and the implications for ion channel correlations and robustness.

Jane Yang,Husain Shakil,Stéphanie Ratté,Steven A Prescott

doi:10.7554/elife.72875

Abstract

Neurons regulate their excitability by adjusting their ion channel levels. Degeneracy - achieving equivalent outcomes (excitability) using different solutions (channel combinations) - facilitates this regulation by enabling a disruptive change in one channel to be offset by compensatory changes in other channels. But neurons must coregulate many properties. Pleiotropy - the impact of one channel on more than one property - complicates regulation because a compensatory ion channel change that restores one property to its target value often disrupts other properties. How then does a neuron simultaneously regulate multiple properties? Here, we demonstrate that of the many channel combinations producing the target value for one property (the single-output solution set), few combinations produce the target value for other properties. Combinations producing the target value for two or more properties (the multioutput solution set) correspond to the intersection between single-output solution sets. Properties can be effectively coregulated only if the number of adjustable channels (nin) exceeds the number of regulated properties (nout). Ion channel correlations emerge during homeostatic regulation when the dimensionality of solution space (nin - nout) is low. Even if each property can be regulated to its target value when considered in isolation, regulation as a whole fails if single-output solution sets do not intersect. Our results also highlight that ion channels must be coadjusted with different ratios to regulate different properties, which suggests that each error signal drives modulatory changes independently, despite those changes ultimately affecting the same ion channels.

Highlights

Neurons maintain their average firing rate near a target value, or set point, by adjusting their intrinsic excitability and synaptic weights[1-6]
Ion channel degeneracy facilitates robust homeostatic regulation of neuronal excitability by enabling a disruptive change in one ion channel to be offset by compensatory changes in other ion channels[22, 34, 35, 45-50]
Replacing native IM with virtual IM did not affect firing pattern, quantified as the coefficient of variation of the interspike interval (CVISI), whereas virtual inserting a virtual calcium-activated AHP-type K+ current (IAHP) reduced CVISI (Fig. 2F), often causing the neuron to spike at different times than the neuron with native or virtual IM (Fig. 2G)

Summary

Introduction

Neurons maintain their average firing rate near a target value, or set point, by adjusting their intrinsic excitability and synaptic weights[1-6]. Homeostatic regulation of intrinsic excitability is achieved through feedback control of diverse ion channels[1, 2, 4, 7]. Computational models have successfully employed negative feedback to adjust ion channel densities[8-12] and control theory provides a valuable framework to conceptualize how this occurs[13]. Most of the mechanistic details remain unclear[14, 15] and are not straightforward; for instance, different perturbations can trigger similar changes in excitability via different signaling pathways affecting different ion channels[16], or via different combinations of excitability changes and synaptic scaling[17]. Firing rate homeostasis is facilitated by the ability of different ion channel combinations to produce equivalent excitability[18]. Ion channel degeneracy facilitates robust homeostatic regulation of neuronal excitability by enabling a disruptive change in one ion channel to be offset by compensatory changes in other ion channels[22, 34, 35, 45-50]

Methods

Results

Conclusion