Affiliation:
1. Molecular, Cellular and Integrative Neurosciences Program, Colorado State University
2. Department of Biomedical Sciences, Colorado State University,
3. Department of Cell Biology, New York University Grossman School of Medicine
Abstract
Ketamine is shown to enhance excitatory synaptic drive in multiple brain areas, which is presumed to underlie its rapid antidepressant effects. Moreover, ketamine’s therapeutic actions are likely mediated by enhancing neuronal Ca2+ signaling. However, ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist that reduces excitatory synaptic transmission and postsynaptic Ca2+ signaling. Thus, it is a puzzling question how ketamine enhances glutamatergic and Ca2+ activity in neurons to induce rapid antidepressant effects while blocking NMDARs in the hippocampus. Here, we find that ketamine treatment in cultured mouse hippocampal neurons significantly reduces Ca2+ and calcineurin activity to elevate AMPA receptor (AMPAR) subunit GluA1 phosphorylation. This phosphorylation ultimately leads to the expression of Ca2+-Permeable, GluA2-lacking, and GluA1-containing AMPARs (CP-AMPARs). The ketamine-induced expression of CP-AMPARs enhances glutamatergic activity and glutamate receptor plasticity in cultured hippocampal neurons. Moreover, when a sub-anesthetic dose of ketamine is given to mice, it increases synaptic GluA1 levels, but not GluA2, and GluA1 phosphorylation in the hippocampus within 1 hr after treatment. These changes are likely mediated by ketamine-induced reduction of calcineurin activity in the hippocampus. Using the open field and tail suspension tests, we demonstrate that a low dose of ketamine rapidly reduces anxiety-like and depression-like behaviors in both male and female mice. However, when in vivo treatment of a CP-AMPAR antagonist abolishes the ketamine’s effects on animals’ behaviors. We thus discover that ketamine at the low dose promotes the expression of CP-AMPARs via reduction of calcineurin activity, which in turn enhances synaptic strength to induce rapid antidepressant actions.
Funder
Colorado State University
Boettcher Foundation
NIH/NCATS Colorado CTSA Grant
NIA
BrightFocus Foundation
Publisher
eLife Sciences Publications, Ltd
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience
Reference152 articles.
1. Ketamine's mechanism of action: a path to rapid-acting antidepressants;Abdallah;Depression and Anxiety,2016
2. The effects of acute and repeated administration of ketamine on memory, behavior, and plasma corticosterone levels in female mice;Acevedo;Neuroscience,2023
3. Α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic acid receptor plasticity sustains severe, fatal status epilepticus;Adotevi;Annals of Neurology,2020
4. Effect of ketamine on exploratory behaviour in BALB/C and C57Bl/6 mice;Akillioglu;Pharmacology, Biochemistry, and Behavior,2012
5. Effect neonatal ketamine treatment on exploratory and anxiety-like behaviours in adulthood;Akillioglu;Clinical Psychopharmacology and Neuroscience,2021
Cited by
3 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献