Ketamine enhances structural plasticity in mouse mesencephalic and human iPSC-derived dopaminergic neurons via AMPAR-driven BDNF and mTOR signaling

• Published in: Molecular psychiatry Vol. 23; no. 4; pp. 812 - 823
• Main Authors: Cavalleri, L, Merlo Pich, E, Millan, M J, Chiamulera, C, Kunath, T, Spano, P F, Collo, G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2018; Nature Publishing Group
• Subjects: 13/51; 14/1; 14/63; 631/378; 631/45; 631/532; 64/60; 96/100; Activation; Allosteric properties; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - metabolism; Animals; Antidepressive Agents - pharmacology; Behavioral Sciences; Biological Psychology; Brain - metabolism; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Cellular signal transduction; Data processing; Dendritic branching; Dopamine D3 receptors; Dopamine receptors; Dopaminergic Neurons - drug effects; Dosage and administration; Hippocampus; Hippocampus - metabolism; Humans; Induced Pluripotent Stem Cells - drug effects; Ketamine; Ketamine - metabolism; Ketamine - pharmacology; Medicine; Medicine & Public Health; Mesencephalon - drug effects; Mice; Mice, Inbred C57BL; Mice, Knockout; Mood; Neuronal Plasticity - drug effects; Neurons; Neurosciences; original-article; Pharmacotherapy; Plastic properties; Plasticity; Pluripotency; Protein biosynthesis; Psychiatry; Rapamycin; Receptors, AMPA - drug effects; Receptors, AMPA - metabolism; Receptors, Dopamine D3 - metabolism; Receptors, Glutamate - drug effects; Ribosomal protein S6 kinase; Signal Transduction - drug effects; Stem cell transplantation; Stem cells; TOR protein; TOR Serine-Threonine Kinases - metabolism; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2017.241

Among neurobiological mechanisms underlying antidepressant properties of ketamine, structural remodeling of prefrontal and hippocampal neurons has been proposed as critical. The suggested mechanism involves downstream activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which trigger mammalian target of rapamycin (mTOR)-dependent structural plasticity via brain-derived neurotrophic factor (BDNF) and protein neo-synthesis. We evaluated whether ketamine elicits similar molecular events in dopaminergic (DA) neurons, known to be affected in mood disorders, using a novel, translational strategy that involved mouse mesencephalic and human induced pluripotent stem cells-derived DA neurons. Sixty minutes exposure to ketamine elicited concentration-dependent increases of dendritic arborization and soma size in both mouse and human cultures as measured 72 hours after application. These structural effects were blocked by mTOR complex/signaling inhibitors like rapamycin. Direct evidence of mTOR activation by ketamine was revealed by its induction of p70S6 kinase. All effects of ketamine were abolished by AMPA receptor antagonists and mimicked by the AMPA-positive allosteric modulator CX614. Inhibition of BDNF signaling prevented induction of structural plasticity by ketamine or CX614. Furthermore, the actions of ketamine required functionally intact dopamine D3 receptors (D3R), as its effects were abolished by selective D3R antagonists and absent in D3R knockout preparations. Finally, the ketamine metabolite (2R,6R)-hydroxynorketamine mimicked ketamine effects at sub-micromolar concentrations. These data indicate that ketamine elicits structural plasticity by recruitment of AMPAR, mTOR and BDNF signaling in both mouse mesencephalic and human induced pluripotent stem cells-derived DA neurons. These observations are of likely relevance to the influence of ketamine upon mood and its other functional actions
in vivo
.