Reversal of Age-Related Neuronal Atrophy by α5-GABAA Receptor Positive Allosteric Modulation.

Abstract

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 α5-subunit containing GABA-A receptors (α5-GABAA-Rs) occurs during aging and contributes to cognitive impairment. Here, we aimed to confirm the beneficial effect on working memory of augmenting α5-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 α5-GABAA-R (α5-PAM), increases dendritic branching complexity and spine numbers of cortical neurons in vitro. Using old mice, we confirm that α5-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 α5-GABAA-R function in old mice, suggesting symptomatic and disease-modifying potential in age-related brain disorders.

• Authors: Thomas D Prevot, Akiko Sumitomo, Toshifumi Tomoda, Daniel E Knutson, Guanguan Li, Prithu Mondal, Mounira Banasr, James M Cook, Etienne Sibille
• Journal: Cerebral cortex (New York, N.Y. : 1991) (Cereb Cortex) Vol. 31 Issue 2 Pg. 1395-1408 (01 05 2021) ISSN: 1460-2199 [Electronic] United States
• PMID: 33068001 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• GABA Modulators
• Gabra5 protein, mouse
• Receptors, GABA-A

Topics

• Aging (drug effects, pathology, physiology)
• Allosteric Regulation (drug effects, physiology)
• Animals
• Atrophy
• Cells, Cultured
• Cerebral Cortex (drug effects, pathology, physiology)
• Female
• GABA Modulators (chemistry, pharmacology)
• Memory, Short-Term (drug effects, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neurons (drug effects, pathology, physiology)
• Pregnancy
• Receptors, GABA-A (physiology)