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Therapeutic efforts aimed at reversing these deficits have focused on excitatory or neurotrophic mechanisms, although recent findings show that reduced dendritic inhibition mediated by \u03b15-subunit containing GABA-A receptors (\u03b15-GABAA-Rs) occurs during aging and contributes to cognitive impairment. Here, we aimed to confirm the beneficial effect on working memory of augmenting \u03b15-GABAA-R activity in old mice and tested its potential at reversing age-related neuronal atrophy. We show that GL-II-73, a novel ligand with positive allosteric modulatory activity at \u03b15-GABAA-R (\u03b15-PAM), increases dendritic branching complexity and spine numbers of cortical neurons in vitro. Using old mice, we confirm that \u03b15-PAM reverses age-related working memory deficits and show that chronic treatment (3\u00a0months) significantly reverses age-related dendritic shrinkage and spine loss in frontal cortex and hippocampus. A subsequent 1-week treatment cessation (separate cohort) resulted in loss of efficacy on working memory but maintained morphological neurotrophic effects. Together, the results demonstrate the beneficial effect on working memory and neurotrophic efficacy of augmenting \u03b15-GABAA-R function in old mice, suggesting symptomatic and disease-modifying potential in age-related brain disorders.<\/jats:p>","DOI":"10.1093\/cercor\/bhaa310","type":"journal-article","created":{"date-parts":[[2020,9,22]],"date-time":"2020-09-22T22:56:20Z","timestamp":1600815380000},"page":"1395-1408","source":"Crossref","is-referenced-by-count":40,"title":["Reversal of Age-Related Neuronal Atrophy by \u03b15-GABAA Receptor Positive Allosteric Modulation"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6774-603X","authenticated-orcid":false,"given":"Thomas D","family":"Prevot","sequence":"first","affiliation":[{"name":"Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, 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Milwaukee, WI 53211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prithu","family":"Mondal","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Wisconsin\u2013Milwaukee, Milwaukee, WI 53211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mounira","family":"Banasr","sequence":"additional","affiliation":[{"name":"Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada"},{"name":"Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada"},{"name":"Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M","family":"Cook","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Wisconsin\u2013Milwaukee, Milwaukee, WI 53211, 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