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However, the underlying molecular mechanism remains unknown. Here we show that, in mouse lines carrying Alzheimer's disease-related mutations, a loss of neuronal membrane potassium-chloride cotransporter KCC2, responsible for maintaining the robustness of GABAA-mediated inhibition, occurs pre-symptomatically in the hippocampus and prefrontal cortex.<\/jats:p>\n               <jats:p>KCC2 downregulation was inversely correlated with the age-dependent increase in amyloid-\u03b2 42 (A\u03b242). Acute administration of A\u03b242 caused a downregulation of membrane KCC2. Loss of KCC2 resulted in impaired chloride homeostasis. Preventing the decrease in KCC2 using long term treatment with CLP290 protected against deterioration of learning and cortical hyperactivity. In addition, restoring KCC2, using short term CLP290 treatment, following the transporter reduction effectively reversed spatial memory deficits and social dysfunction, linking chloride dysregulation with Alzheimer's disease-related cognitive decline.<\/jats:p>\n               <jats:p>These results reveal KCC2 hypofunction as a viable target for treatment of Alzheimer's disease-related cognitive decline; they confirm target engagement, where the therapeutic intervention takes place, and its effectiveness.<\/jats:p>","DOI":"10.1093\/brain\/awad250","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T08:09:08Z","timestamp":1691482148000},"page":"4903-4915","source":"Crossref","is-referenced-by-count":37,"title":["Restoring neuronal chloride extrusion reverses cognitive decline linked to Alzheimer\u2019s disease 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