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

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.Molecular Psychiatry advance online publication, 21 November 2017; doi:10.1038/mp.2017.241

[XVI-Sichem] Melchior Hofman Van Strasbvrg

Retrat

[XVI-Sichem] ...drick Nicolaes T. Hvys der Liefden

Retrat

A generall historie of the Netherlands [electronic resource] : VVith the genealogie and memorable acts of the Earls of Holland, Zeeland, and west-Friseland, from Thierry of Aquitaine the first Earle, successiuely vnto Philip the third King of Spaine: continued vnto this present yeare of our Lord 1608, out of the best authors that haue written of that subiect: by Ed. Grimeston.

Largely a translation of: Le Petit, Jean Franðcois. La grande chronique.In this edition Grimeston includes a translation of Le Petit's preface from "La grande chronique" and mentions in the translator's preface that the continuation of the history is derived from "Historia Belgica nostri potissimum temporis" by Emmanuel van Meteren.Eld printed quires O-2D, 3A-3P, 4I-5F, 5X-6C, and possibly the index; Islip printed the rest (STC).The engraved title-page border and many of the fifty-seven portraits are signed by Christoffel van Sichem and were originally published in Le Petit's "La grande chronique".The first leaf and the last leaf are blank.Includes index.P. 1413 misnumbered 1415.A variant (STC 12375) is dated 1609.Reproduction of the original in the Henry E. Huntington Library and Art Gallery.Some foxing and light print. Pages 1342-1345 spotted; page 595 folded in printing, affecting text.STC (2nd ed.)Electronic reproduction