A role of GABAA receptor α1 subunit in the hippocampus for rapid-acting antidepressant-like effects of ketamine.
Neuropharmacology December 21, 2022 Xiao-Hui Tang, Y. Diao, Zhuoying Ren et al.
Ketamine produces rapid antidepressant-like effects in mice exposed to forced swimming stress. The stressed mice showed depression-like behavior and reduced GABA levels in the hippocampus. Ketamine increased GABA and decreased glutamate there, and GABA levels correlated with behavior. Ketamine raised levels of certain GABAergic enzymes and transporters and astrocytic proteins, but not those on glutamatergic neurons. It also decreased the GABAAR α1 subunit, boosted GABA synthesis and metabolism, altered astrocyte plasticity, and increased ATP. A GABAAR antagonist or ATP itself had rapid antidepressant-like effects, while a GABAAR agonist blocked ketamine's effects. The findings suggest ketamine works by downregulating GABAAR α1, increasing GABA, and converting GABA to ATP.