Yang Jane, Prescott Steven A
Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada.
Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada.
Front Cell Neurosci. 2023 Jun 2;17:1184563. doi: 10.3389/fncel.2023.1184563. eCollection 2023.
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.
尽管环境不断变化，神经元仍能将其平均放电率和其他特性维持在狭窄的范围内。这种稳态调节是通过负反馈来调整离子通道表达水平实现的。为了理解兴奋性的稳态调节正常情况下是如何工作的，以及它是如何出错的，人们必须考虑所涉及的各种离子通道，以及在调节兴奋性时调整这些通道所影响的其他被调节特性。这就引发了简并性和多效性的问题。简并性是指不同的解决方案传达相同的功能（例如，不同的通道组合产生相同的兴奋性）。这种多对一的映射与多效性所描述的一对多映射形成对比（例如，一个通道影响多种特性）。简并性通过使干扰能够被几种不同通道中的任何一种或其组合的补偿性变化抵消，从而促进稳态调节。多效性使稳态调节变得复杂，因为旨在调节一种特性的补偿性变化可能会无意中干扰其他特性。通过调整多效性通道共同调节多种特性比单独调节一种特性需要更高的简并性，并且进而可能由于诸如每种特性的解决方案相互不兼容等其他原因而失败。如果扰动太强和/或负反馈太弱，或者因为设定点受到干扰，也会出现问题。描绘反馈回路及其相互作用为稳态调节可能如何失败提供了有价值的见解。鉴于不同的失败模式需要不同的干预措施来恢复稳态，对稳态调节及其病理破坏的更深入理解可能会揭示出针对神经性疼痛和癫痫等慢性神经疾病更有效的治疗方法。
