Throughout the nervous system, ion gradients drive fundamental processes. Yet, the roles of interstitial ions in brain functioning is largely forgotten. Emerging literature is now revitalizing this area of neuroscience by showing that interstitial cations (K⁺, Ca²⁺ and Mg²⁺) are not static quantities but change dynamically across states such as sleep and locomotion. In turn, these state-dependent changes are capable of sculpting neuronal activity; for example, changing the local interstitial ion composition in the cortex is sufficient for modulating the prevalence of slow-frequency neuronal oscillations, or potentiating the gain of visually evoked responses. Disturbances in interstitial ionic homeostasis may also play a central role in the pathogenesis of central nervous system diseases. For example, impairments in K⁺ buffering occur in a number of neurodegenerative diseases, and abnormalities in neuronal activity in disease models disappear when interstitial K⁺ is normalized. Here we provide an overview of the roles of interstitial ions in physiology and pathology. We propose the brain uses interstitial ion signaling as a global mechanism to coordinate its complex activity patterns, and ion homeostasis failure contributes to central nervous system diseases affecting cognitive functions and behavior.

在整个神经系统中，离子梯度驱动基本过程。然而，间隙离子在大脑功能中的作用在很大程度上被遗忘了。新兴文献现在通过表明间隙阳离子（K ⁺、Ca ²⁺和 Mg ²⁺) 不是静态量，而是在睡眠和运动等状态下动态变化。反过来，这些状态相关的变化能够塑造神经元活动；例如，改变皮层中的局部间隙离子组成足以调节慢频神经元振荡的流行，或增强视觉诱发反应的增益。间质离子稳态的紊乱也可能在中枢神经系统疾病的发病机制中起核心作用。例如，K ⁺缓冲受损发生在许多神经退行性疾病中，当间质性 K ⁺时，疾病模型中神经元活动的异常消失被归一化。在这里，我们概述了间隙离子在生理学和病理学中的作用。我们建议大脑使用间质离子信号作为全局机制来协调其复杂的活动模式，而离子稳态失败会导致影响认知功能和行为的中枢神经系统疾病。