期刊
CEREBRAL CORTEX
卷 31, 期 2, 页码 1395-1408出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/cercor/bhaa310
关键词
aging; cognition; GABA; neurotrophic effect; positive allosteric modulator
资金
- Centre for Addiction and Mental Health
- Campbell Family Mental Health Research Institute
- National Institutes of Health [DA-043204, R01NS076517, R01HL118561]
- University of Wisconsin-Milwaukee's Shimadzu Laboratory for Advanced and Applied Analytical Chemistry
- National Science Foundation, Division of Chemistry [CHE-1625735]
Aging is associated with brain volume reduction, altered neural activity, and neuronal atrophy, leading to cognitive impairments. Augmenting alpha(5)-GABAA-R function has beneficial effects on working memory in old mice and may reverse age-related neuronal atrophy.
Aging is associated with reduced brain volume, altered neural activity, and neuronal atrophy in cortical-like structures, comprising the frontal cortex and hippocampus, together contributing to cognitive impairments. Therapeutic efforts aimed at reversing these deficits have focused on excitatory or neurotrophic mechanisms, although recent findings show that reduced dendritic inhibition mediated by alpha(5)-subunit containing GABA-A receptors (alpha(5)-GABAA-Rs) occurs during aging and contributes to cognitive impairment. Here, we aimed to confirm the beneficial effect on working memory of augmenting alpha(5)-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 alpha(5)-GABAA-R (alpha(5)-PAM), increases dendritic branching complexity and spine numbers of cortical neurons in vitro. Using old mice, we confirm that alpha(5)-PAM reverses age-related working memory deficits and show that chronic treatment (3 months) 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 alpha(5)-GABAA-R function in old mice, suggesting symptomatic and disease-modifying potential in age-related brain disorders.
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