Ketamine enhances structural plasticity in mouse mesencephalic and human iPSC-derived dopaminergic neurons via AMPAR-driven BDNF and mTOR signaling
| Autor: | Laura Cavalleri, PierFranco Spano, E Merlo Pich, Christian Chiamulera, Millan Mark, Tilo Kunath, Ginetta Collo |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
CX614 Allosteric modulator Hydroxynorketamine Induced Pluripotent Stem Cells AMPA receptor Hippocampus D3 receptor 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound Mice 0302 clinical medicine Dopamine receptor D3 Neurotrophic factors Mesencephalon AMPA Animals Humans Receptors AMPA Molecular Biology alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid PI3K/AKT/mTOR pathway Mice Knockout iPSC Neuronal Plasticity Brain-Derived Neurotrophic Factor Dopaminergic Neurons TOR Serine-Threonine Kinases Dopaminergic Receptors Dopamine D3 Brain structural plasticity Antidepressive Agents Mice Inbred C57BL Psychiatry and Mental health Ketamine dopaminergic neurons structural plasticity iPSC BDNF AMPA D3 receptor depression 030104 developmental biology BDNF chemistry nervous system Receptors Glutamate depression Ketamine Neuroscience 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Cavalleri, L, Merlo Pich, E, Millan, M J, Chiamulera, C, Kunath, T, Spano, P F & Collo, G 2017, ' Ketamine enhances structural plasticity in mouse mesencephalic and human iPSC-derived dopaminergic neurons via AMPAR-driven BDNF and mTOR signaling ', Molecular Psychiatry, vol. 23, no. 4, pp. 812-823 . https://doi.org/10.1038/mp.2017.241 |
| ISSN: | 1476-5578 |
| DOI: | 10.1038/mp.2017.241 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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