Chronic α5-GABA-A Receptor Potentiation Promotes Mouse Adult Hippocampal Neurogenesis
Thomas D Prevot1,2,3, Michael Marcotte1, Denis J David4
1Campbell Family Mental Health Research Institute of CAMH, Toronto, Ontario, Canada.
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Summary
A novel drug targeting the α5-GABAA receptor (α5-PAM) significantly boosted adult hippocampal neurogenesis (AHN) in mice. This effect, comparable to fluoxetine, involved increased cell proliferation, survival, and maturation of new neurons.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Adult hippocampal neurogenesis (AHN) is crucial for cognitive and mood-related behaviors.
- Augmenting α5-γ-Aminobutyric acid type A (GABAA) receptor function shows promise for neurotrophic effects.
- The impact of α5-GABAA receptor modulation on AHN is not well understood.
Purpose of the Study:
- To investigate the effect of a novel α5-GABAA-R positive allosteric modulator (α5-PAM), GL-II-73, on adult mouse hippocampal neurogenesis.
- To compare the impact of GL-II-73 on AHN with fluoxetine, a known enhancer of neurogenesis.
Main Methods:
- Adult male mice were treated for 6 weeks with either GL-II-73 (α5-PAM) or fluoxetine.
- Cell proliferation was assessed using Ki67.
- Newborn neuron survival and maturation were evaluated using 5-Bromo-2´-Deoxyuridine (BrdU) retention and co-labeling with DCX and NeuN.
Main Results:
- Chronic treatment with GL-II-73 significantly increased neuronal progenitor proliferation in the dentate gyrus (DG).
- GL-II-73 enhanced the survival of adult-born granule cells.
- The maturation rate of young adult-born neurons was also increased by GL-II-73 treatment.
Conclusions:
- GL-II-73, an α5-GABAA-R positive allosteric modulator, effectively stimulates all stages of adult hippocampal neurogenesis.
- The neurogenic effects of GL-II-73 are comparable to those of fluoxetine.
- Targeting α5-GABAA receptors represents a potential therapeutic strategy for enhancing neurogenesis.