Chronic α5-GABA-A Receptor Potentiation Promotes Mouse Adult Hippocampal Neurogenesis

Area of Science:

• Neuroscience
• Neurogenesis
• Pharmacology

Background:

• Adult hippocampal neurogenesis (AHN) is implicated in cognitive functions, mood regulation, and antidepressant effects.
• Augmenting alpha5-gamma-aminobutyric acid type A (GABAA) receptor function shows neurotrophic potential but its effect on AHN is unknown.

Purpose of the Study:

• To investigate the impact of an alpha5-GABAA-R-positive allosteric modulator (α5-PAM), GL-II-73, on adult hippocampal neurogenesis (AHN) in mice.
• To compare the effects of GL-II-73 on AHN with fluoxetine, a known enhancer of neurogenesis.

Main Methods:

• Adult male mice were treated for 6 weeks with GL-II-73 (an α5-PAM) or fluoxetine.
• Neuronal progenitor proliferation was assessed using Ki67.
• Survival and maturation of new neurons were evaluated using 5-Bromo-2´-Deoxyuridine (BrdU) retention and co-labeling with DCX and/or 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 and promoted the maturation of new neurons.
• The observed increases in AHN stages by GL-II-73 were comparable to those induced by fluoxetine.

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 the selective serotonin reuptake inhibitor fluoxetine.
• Targeting α5-GABAA receptors may represent a novel therapeutic strategy for conditions involving impaired neurogenesis.