Chloride Homeostasis in Neuronal Disorders: Bridging Measurement to Therapy

Neuronal chloride (Cl−) homeostasis is fundamental for brain function, with disruptions increasingly recognized as pathogenic across neurological disorders. This review synthesizes evidence from preclinical models and clinical studies, integrating electrophysiological measurements, molecular analyses, imaging with genetically encoded sensors like ClopHensor, and behavioral assays. Key findings demonstrate that Cl− dysregulation follows distinct patterns: (1) in epilepsy, KCC2 downregulation converts GABAergic inhibition to excitation, promoting seizures; (2) in Alzheimer’s disease (AD) models, pre-symptomatic KCC2 loss in hippocampus is observed, with KCC2 restoration reversing aspects of cognitive decline; (3) in autism spectrum disorders (ASD), developmental delays in GABA polarity shifts feature due to altered NKCC1/KCC2 ratios; and (4) in Huntington’s disease (HD), striatal neuron-specific Cl− imbalances are linked to motor dysfunction. Methodologically, advanced tools—including subcellular Cl− imaging and high-throughput drug screening—have enabled precise dissection of these mechanisms. Therapeutic strategies targeting Cl− transporters (NKCC1 inhibitors like bumetanide, KCC2 enhancers like CLP290) show preclinical promise but require improved central nervous system (CNS) delivery and selectivity. These findings establish Cl− homeostasis as both a biomarker and therapeutic target, necessitating precision medicine approaches to address heterogeneity in neurological disorders.