Homeostatic regulation of neuronal function: importance of degeneracy and pleiotropy

Abstract

Neurons maintain their average firing rate and other properties within narrow bounds despite changing conditions. This homeostatic regulation is achieved using negative feedback to adjust ion channel expression levels. To understand how homeostatic regulation of excitability normally works and how it goes awry, one must consider the various ion channels involved as well as the other regulated properties impacted by adjusting those channels when regulating excitability. This raises issues of degeneracy and pleiotropy. Degeneracy refers to disparate solutions conveying equivalent function (e.g., different channel combinations yielding equivalent excitability). This many-to-one mapping contrasts the one-to-many mapping described by pleiotropy (e.g., one channel affecting multiple properties). Degeneracy facilitates homeostatic regulation by enabling a disturbance to be offset by compensatory changes in any one of several different channels or combinations thereof. Pleiotropy complicates homeostatic regulation because compensatory changes intended to regulate one property may inadvertently disrupt other properties. Co-regulating multiple properties by adjusting pleiotropic channels requires greater degeneracy than regulating one property in isolation and, by extension, can fail for additional reasons such as solutions for each property being incompatible with one another. Problems also arise if a perturbation is too strong and/or negative feedback is too weak, or because the set point is disturbed. Delineating feedback loops and their interactions provides valuable insight into how homeostatic regulation might fail. Insofar as different failure modes require distinct interventions to restore homeostasis, deeper understanding of homeostatic regulation and its pathological disruption may reveal more effective treatments for chronic neurological disorders like neuropathic pain and epilepsy.

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

“…The overall approach employed here could be used to build different heterogeneous populations of granule cells built with distinct morphologies and disparate sets of ion channels that emerge from respective experimental measurements that span a large set of characteristics from the same set of cells. Such analyses would enable a fundamental understanding of differences in heterogeneities, composition, extent of degeneracy in each state, and how they contribute to the physiology of the neurons and their networks (Ratté et al, 2014; Ratte and Prescott, 2016; Goaillard and Marder, 2021; Mishra and Narayanan, 2021d; Seenivasan and Narayanan, 2022; Marom and Marder, 2023; Mittag et al, 2023; Stober et al, 2023; Yang and Prescott, 2023).…”

Similar excitability through different sodium channels and implications for the analgesic efficacy of selective drugs

“…To be interchangeable, Na V subtypes must functionally overlap ( Goaillard and Marder, 2021 ; Yang and Prescott, 2023 ). Indeed, Na V 1.8 and Na V 1.7 are similar but not identical in their gating properties; for example, their voltage-dependencies partially overlap but the activation curve for Na V 1.8 is right-shifted compared to Na V 1.7 ( Schild and Kunze, 1997 ).…”

Ih current stabilizes excitability in rodent DRG neurons and reverses hyperexcitability in a nociceptive neuron model of inherited neuropathic pain

“…Given the degeneracy that exists in terms of ion channel expression in most types of neurons, i.e. the expression of multiple ion channels with overlapping voltage‐ and time‐dependent properties, with cell‐to‐cell differences in level of expression for many of these channels (Drion et al., 2015; Goaillard & Marder, 2021; Yang & Prescott, 2023), we cannot exclude the contributions of other channels to the current‐clamp observations we describe. Nevertheless, our results provide strong evidence of a functionally important interaction between I h and Nav1.7 and demonstrate that I h can reverse the hyperexcitability of DRG neurons expressing the L858H gain‐of‐function mutation of Nav1.7, a human genetic model of neuropathic pain.…”