{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T19:01:06Z","timestamp":1794078066075,"version":"4.8.0"},"reference-count":152,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,21]],"date-time":"2021-08-21T00:00:00Z","timestamp":1629504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>In neuronal precursors and immature neurons, the depolarizing (excitatory) effect of \u03b3-Aminobutyric acid (GABA) signaling is associated with elevated [Cl\u2212]i; as brain cells mature, a developmental switch occurs, leading to the decrease of [Cl\u2212]i and to the hyperpolarizing (inhibitory) effect of GABAergic signaling. [Cl\u2212]i is controlled by two chloride co-transporters: NKCC1, which causes Cl\u2212 to accumulate into the cells, and KCC2, which extrudes it. The ontogenetic upregulation of the latter determines the above-outlined switch; however, many other factors contribute to the correct [Cl\u2212]i in mature neurons. The dysregulation of chloride homeostasis is involved in seizure generation and has been associated with schizophrenia, Down\u2019s Syndrome, Autism Spectrum Disorder, and other neurodevelopmental disorders. Recently, much effort has been put into developing new drugs intended to inhibit NKCC1 activity, while no attention has been paid to the origin of [Cl\u2212]i dysregulation. Our study examines the pathophysiology of Cl\u2212 homeostasis and focuses on the impact of oxidative stress (OS) and inflammation on the activity of Cl\u2212 co-transporters, highlighting the relevance of OS in numerous brain abnormalities and diseases. This hypothesis supports the importance of primary prevention during pregnancy. It also integrates the therapeutic framework addressed to restore normal GABAergic signaling by counteracting the alteration in chloride homeostasis in central nervous system (CNS) cells, aiming at limiting the use of drugs that potentially pose a health risk.<\/jats:p>","DOI":"10.3390\/antiox10081316","type":"journal-article","created":{"date-parts":[[2021,8,22]],"date-time":"2021-08-22T21:42:12Z","timestamp":1629668532000},"page":"1316","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["The Alteration of Chloride Homeostasis\/GABAergic Signaling in Brain Disorders: Could Oxidative Stress Play a Role?"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5242-9448","authenticated-orcid":false,"given":"Provvidenza M.","family":"Abruzzo","sequence":"first","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine, School of Medicine, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9561-1258","authenticated-orcid":false,"given":"Cristina","family":"Panisi","sequence":"additional","affiliation":[{"name":"Fondazione Istituto Sacra Famiglia, Cesano Boscone, 20090 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1932-7380","authenticated-orcid":false,"given":"Marina","family":"Marini","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine, School of Medicine, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6257","DOI":"10.1073\/pnas.0931278100","article-title":"The Na\/K pump, Cl ion, and osmotic stabilization of cells","volume":"100","author":"Armstrong","year":"2003","journal-title":"Proc. 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