{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T01:10:53Z","timestamp":1793149853059,"version":"4.5.0"},"reference-count":162,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T00:00:00Z","timestamp":1758067200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondazione CARIVERONA, Verona, Italy"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Neuronal chloride (Cl\u2212) 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\u2212 dysregulation follows distinct patterns: (1) in epilepsy, KCC2 downregulation converts GABAergic inhibition to excitation, promoting seizures; (2) in Alzheimer\u2019s 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\u2019s disease (HD), striatal neuron-specific Cl\u2212 imbalances are linked to motor dysfunction. Methodologically, advanced tools\u2014including subcellular Cl\u2212 imaging and high-throughput drug screening\u2014have enabled precise dissection of these mechanisms. Therapeutic strategies targeting Cl\u2212 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\u2212 homeostasis as both a biomarker and therapeutic target, necessitating precision medicine approaches to address heterogeneity in neurological disorders.<\/jats:p>","DOI":"10.3390\/life15091461","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T15:12:44Z","timestamp":1758121964000},"page":"1461","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Chloride Homeostasis in Neuronal Disorders: Bridging Measurement to Therapy"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2872-6906","authenticated-orcid":false,"given":"Daniele","family":"Arosio","sequence":"first","affiliation":[{"name":"Istituto di Biofisica, Consiglio Nazionale delle Ricerche, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2106-9931","authenticated-orcid":false,"given":"Carlo","family":"Musio","sequence":"additional","affiliation":[{"name":"Istituto di Biofisica, Consiglio Nazionale delle Ricerche, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/epi.12034","article-title":"Regulators of Synaptic Transmission: Roles in the Pathogenesis and Treatment of Epilepsy","volume":"53","author":"Powell","year":"2012","journal-title":"Epilepsia"},{"key":"ref_2","unstructured":"Kandel, E.R., Koester, J., Mack, S., and Siegelbaum, S. 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