Homeostatic regulation of neuronal function: importance of degeneracy and pleiotropy

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.