Double-edged Role of K_Na Channels in Brain Tuning: Identifying Epileptogenic Network Micro-Macro Disconnection

Epilepsy is commonly recognized as a disease driven by generalized hyperexcited and hypersynchronous neural activity. Sodium-activated potassium channels (K_Na channels), which are encoded by the Slo 2.2 and Slo 2.1 genes, are widely expressed in the central nervous system and considered as "brakes" to adjust neuronal adaptation through regulating action potential threshold or after-hyperpolarization under physiological condition. However, the variants in K_Na channels, especially gain-of-function variants, have been found in several childhood epileptic conditions. Most previous studies focused on mapping the epileptic network on the macroscopic scale while ignoring the value of microscopic changes. Notably, paradoxical role of K_Na channels working on individual neuron/microcircuit and the macroscopic epileptic expression highlights the importance of understanding epileptogenic network through combining microscopic and macroscopic methods. Here, we first illustrated the molecular and physiological function of K_Na channels on preclinical seizure models and patients with epilepsy. Next, we summarized current hypothesis on the potential role of K_Na channels during seizures to provide essential insight into what emerged as a micro-macro disconnection at different levels. Additionally, we highlighted the potential utility of K_Na channels as therapeutic targets for developing innovative anti-seizure medications.