A role of GABAA receptor α1 subunit in the hippocampus for rapid-acting antidepressant-like effects of ketamine. (1st March 2023)

• Record Type: Journal Article
• Authors: Tang, Xiao-Hui; Diao, Yu-Gang; Ren, Zhuo-Yu; Zang, Yan-Yu; Zhang, Guang-Fen; Wang, Xing-Ming; Duan, Gui-Fang; Shen, Jin-Chun; Hashimoto, Kenji; Zhou, Zhi-Qiang; Yang, Jian-Jun
• Is Part Of: Neuropharmacology. Volume 225(2023)
• Publication Date: 2023-03-01
• Subjects: Ketamine -- Antidepressant -- Astrocyte -- Glutamate -- GABA -- GABAAR α1; ALDH5A1 succinic semialdehyde dehydrogenase -- ATP adenosine triphosphate -- BCA bicinchoninic acid -- CSDS chronic social defeat stress -- CSF cerebrospinal fluid -- EAAT2 glutamate transporter excitatory amino acid transporter 2 -- FST forced swimming test -- FSS forced swimming stress -- GABA 67/65 glutamate decarboxylase67/65 -- GS glutamine synthase -- GABA γ-aminobutyric acid -- GAT1 GABA transporter subtype 1 -- GAT3 GABA transporter subtype 3 -- mPFC medial prefrontal cortex -- MDD major depressive disorder -- MRS magnetic resonance spectroscopy -- NMDAR N-methyl-D-aspartate receptor -- OFT open field test -- SAT2 system A transporter subtype 2 -- SSRIs selective serotonin reuptake inhibitors -- SNRIs serotonin norepinephrine reuptake inhibitors -- SAT1 system A transporter subtype 1 -- TCA tricarboxylic acid cycle -- VGLUT vesicular glutamate transporter -- VGAT vesicular GABA transporter; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2022.109383
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Ketamine can produce rapid-acting antidepressant effects in treatment-resistant patients with depression. Although alterations in glutamatergic and GABAergic neurotransmission in the brain play a role in depression, the precise molecular mechanisms in these neurotransmission underlying ketamine's antidepressant actions remain largely unknown. Mice exposed to FSS (forced swimming stress) showed depression-like behavior and decreased levels of GABA (γ-aminobutyric acid), but not glutamate, in the hippocampus. Ketamine increased GABA levels and decreased glutamate levels in the hippocampus of mice exposed to FSS. There was a correlation between GABA levels and depression-like behavior. Furthermore, ketamine increased the levels of enzymes and transporters on the GABAergic neurons (SAT1, GAD67, GAD65, VGAT and GAT1) and astrocytes (EAAT2 and GAT3), without affecting the levels of enzymes and transporters (SAT2, VGluT1 and GABAA R γ2) on glutamatergic neurons. Moreover, ketamine caused a decreased expression of GABAA R α1 subunit, which was specifically expressed on GABAergic neurons and astrocytes, an increased GABA synthesis and metabolism in GABAergic neurons, a plasticity change in astrocytes, and an increase in ATP (adenosine triphosphate) contents. Finally, GABAA R antagonist bicuculline or ATP exerted a rapid antidepressant-like effect whereas pretreatment with GABAA R agonist muscimol blocked the antidepressant-like effects of ketamine. In addition, pharmacological activation and inhibition of GABAA R modulated the synthesis and metabolism of GABA, and the plasticity of astrocytes in the hippocampus. The present data suggest that ketamine could increase GABA synthesis and astrocyte plasticity through downregulation of GABAA R α1, increases in GABA, and conversion of GABA into ATP, resulting in a rapid-acting antidepressant-like action. This article is part of the Special Issue on 'Ketamine and its Metabolites'. Highlights: There was a correlation between GABA levels and depression-like behavior. GABAA receptor α1 subunit in the hippocampus play a role in the antidepressant-like effects of ketamine. Ketamine could increase GABA synthesis and astrocyte plasticity through downregulation of GABAA R α1.