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

Abstract

Several lines of evidence implicate adult hippocampal neurogenesis (AHN) in cognitive functions, in mood- and anxiety-related behaviors, and in the therapeutic effects of antidepressants. Augmenting α5-γ-Aminobutyric acid type A (GABAA) receptor function has shown neurotrophic effects in stress and aged models, but its impact on mouse AHN remains unknown. Adult male 129S6/SvEvTac mice (n = 30 total) were treated for 6 weeks with GL-II-73, an α5-GABAA-R-positive allosteric modulator (α5-PAM) [30 mg/kg, per os, (P.O.)] or fluoxetine, a prototypical selective serotonin reuptake inhibitor known to increase AHN (18 mg/kg, P.O.). Proliferation in the subgranular zone of the dentate gyrus (DG) was assessed by the level of Ki67, a marker of dividing cells; survival of the young neurons was assessed by retention of the 5-Bromo-2´-Deoxyuridine (BrdU) nucleotide analog injected 2 weeks before sacrifice. Finally, maturation of young adult-born neurons was evaluated by measuring the fraction of BrdU-positive cells that are also DCX and/or NeuN-positive, capturing overall maturation and speed of maturation. Similarly to fluoxetine, a chronic treatment with GL-II-73 stimulated all stages of AHN, significantly increasing neuronal progenitor proliferation, survival of adult-born granule cells, and maturation of young neurons in the DG of the hippocampus. Chronic treatment with GL-II-73, a α5-GABAA-R-positive allosteric modulator, increased AHN, including cellular proliferation, survival, and maturation of newborn neurons, to levels comparable to fluoxetine.