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

Molecular Psychiatry volume 23, pages 812–823 (2018)Cite this article

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Abstract

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.

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References

  1. Sinner B, Graf BM . Ketamine. Handb Exp Pharmacol 2008; 182: 313–333.

    Article  CAS  Google Scholar 

  2. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994; 51: 199–214.

    Article  CAS  PubMed  Google Scholar 

  3. Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006; 63: 856–864.

    Article  CAS  PubMed  Google Scholar 

  4. Coyle CM, Laws KR . The use of ketamine as an antidepressant: a systematic review and meta-analysis. Hum Psychopharmacol 2015; 30: 152–163.

    Article  CAS  PubMed  Google Scholar 

  5. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF et al. NMDA receptor blockade at rest triggers rapid behavioral antidepressant responses. Nature 2011; 475: 91–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Browne CA, Lucki I . Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Front Pharmacol 2013; 4: 161.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Yilmaz A, Schulz D, Aksoy A, Canbeyli R . Prolonged effect of an anesthetic dose of ketamine on behavioral despair. Pharmacol Biochem Behav 2002; 71: 341–344.

    Article  CAS  PubMed  Google Scholar 

  8. Krystal JH, Sanacora G, Duman RS . Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry 2013; 73: 1133–1141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Homayoun H, Moghaddam B . NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 2007; 27: 11496–11500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Miller OH, Moran JT, Hall BJ . Two cellular hypotheses explaining the initiation of ketamine's antidepressant actions: Direct inhibition and disinhibition. Neuropharmacology 2016; 100: 17–26.

    Article  CAS  PubMed  Google Scholar 

  11. Maeng S, Zarate CA Jr, Du J, Schloesser R J, Mc Cammon J, Chen G et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5 methylisoxazole-4-propionic acid receptors. Biol Psychiatry 2008; 63: 349–352.

    Article  CAS  PubMed  Google Scholar 

  12. Koike H, Iijima M, Chaki S . Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav Brain Res 2011; 224: 107–111.

    Article  CAS  PubMed  Google Scholar 

  13. Jourdi H, Hsu YT, Zhou M, Qin Q, Bi X, Baudry M . Positive AMPA receptor modulation rapidly stimulates BDNF release and increases dendritic mRNA translation. J Neurosci 2009; 29: 8688–8697.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lepack AE, Fuchikami M, Dwyer JM, Banasr M, Duman RS . BDNF release is required for the behavioral actions of ketamine. Int J Neuropsychopharm 2014; 18: 1–6.

    Google Scholar 

  15. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010; 329: 959–964.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Takei N, Inamura N, Kawamura M, Namba H, Hara K, Yonezawa K et al. Brain-derived neurotrophic factor induces mammalian target of rapamycin dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J Neurosci 2004; 24: 9760–9769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhou W, Wang N, Yang C, Li XM, Zhou ZQ, Yang JJ . Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. Eur Psychiatry 2014; 29: 419–423.

    Article  CAS  PubMed  Google Scholar 

  18. Drevets WC, Price JL, Furey ML . Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct 2008; 213: 93–118.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sanacora G, Treccani G, Popoli M . Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacol 2012; 62: 63–77.

    Article  CAS  Google Scholar 

  20. Jernigan CS, Goswami DB, Austin MC, Iyo AH, Chandran A, Stockmeier CA et al. The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 1774–1779.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Christoffel DJ, Golden SA, Russo SJ . Structural and synaptic plasticity in stress-related disorders. Rev Neurosci 2011; 22: 535–549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Polman JA, Hunter RG, Speksnijder N, van den Oever JM, Korobko OB, McEwen BS et al. Glucocorticoids modulate the mTOR pathway in the hippocampus: differential effects depending on stress history. Endocrinology 2012; 153: 4317–4327.

    Article  CAS  PubMed  Google Scholar 

  23. Chen F, Madsen TM, Wegener G, Nyengaard JR . Repeated electroconvulsive seizures increase the total number of synapses in adult male rat hippocampus. Eur Neuropsychopharmacol 2009; 19: 329–338.

    Article  CAS  PubMed  Google Scholar 

  24. Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry 2009; 14: 764–777.

    Article  CAS  PubMed  Google Scholar 

  25. Dukart J, Regen F, Kherif F, Colla M, Bajbouj M, Heuser I et al. Electroconvulsive therapy-induced brain plasticity determines therapeutic outcome in mood disorders. Proc Natl Acad Sci USA 2014; 111: 1156–1161.

    Article  CAS  PubMed  Google Scholar 

  26. Castrén E, Rantamäki T . The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev Neurobiol 2010; 70: 289–297.

    Article  PubMed  Google Scholar 

  27. Schmidt U, Beyer C, Oestreicher AB, Reisert I, Schilling K, Pilgrim C . Activation of dopaminergic D1 receptor promotes morphogenesis of developing striatal neurons. Neuroscience 1996; 74: 453–460.

    Article  CAS  PubMed  Google Scholar 

  28. Nestler EJ, Carlezon WA . The mesolimbic dopamine reward circuit in depression. J Biol Psychiatry 2006; 59: 1151–1159.

    Article  CAS  Google Scholar 

  29. Der-Avakian A, Mazei-Robison MS, Kesby JP, Nestler EJ, Markou A . Enduring deficits in brain reward function after chronic social defeat in rats: susceptibility, resilience, and antidepressant response. Biol Psychiatry 2014; 76: 542–549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Meyer JH, Krüger S, Wilson AA, Christensen BK, Goulding VS, Schaffer A et al. Lower dopamine transporter binding potential in striatum during depression. Neuroreport 2001; 12: 4121–4125.

    Article  CAS  PubMed  Google Scholar 

  31. Vassout A, Bruinink A, Krauss J, Waldmeier P, Bischoff S . Regulation of dopamine receptors by bupropion: comparison with antidepressants and CNS stimulants. J Recept Res 1993; 13: 341–354.

    Article  CAS  PubMed  Google Scholar 

  32. Leggio GM, Salomone S, Bucolo C, Platania C, Micale V, Caraci F et al. Dopamine D(3) receptor as a new pharmacological target for the treatment of depression. Eur J Pharmacol 2013; 719: 25–33.

    Article  CAS  PubMed  Google Scholar 

  33. Breuer ME, Groenink L, Oosting RS, Buerger E, Korte M, Ferger B et al. Antidepressant effects of pramipexole, a dopamine D3/D2 receptor agonist, and 7-OH-DPAT, a dopamine D3 receptor agonist, in olfactory bulbectomized rats. Eur J Pharmacol 2009; 616: 134–140.

    Article  CAS  PubMed  Google Scholar 

  34. Barone P, Poewe W, Albrecht S, Debieuvre C, Massey D, Rascol O et al. Pramipexole for the treatment of depressive symptoms in patients with Parkinson's disease: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2010; 9: 573–580.

    Article  CAS  PubMed  Google Scholar 

  35. Diaz J, Ridray S, Mignon V, Griffon N, Schwartz JC, Sokoloff P . Selective expression of dopamine D3 receptor mRNA in proliferative zones during embryonic development of the rat brain. J Neurosci 1997; 17: 4282–4292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gurevich EV, Joyce JN . Distribution of dopamine D3 receptor expressing neurons in the human forebrain: comparison with D2 receptor expressing neurons. Neuropsychopharmacology 1999; 20: 60–80.

    Article  CAS  PubMed  Google Scholar 

  37. Sun J, Xu J, Cairns NJ, Perlmutter JS, Mach RH . Dopamine D1, D2, D3 receptors, vesicular monoamine transporter type-2 (VMAT2) and dopamine transporter (DAT) densities in aged human brain. PLoS ONE 2012; 7: e49483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Collo G, Zanetti S, Missale C, Spano PF . Dopamine D3 receptor-preferring agonists increase dendrite arborization of mesencephalic dopaminergic neurons via extracellular signal-regulated kinase phosphorylation. Eur J Neurosci 2008; 28: 1231–1240.

    Article  PubMed  Google Scholar 

  39. Collo G, Bono F, Cavalleri L, Plebani L, Merlo Pich E, Millan MJ et al. Pre-synaptic dopamine D3 receptor mediates cocaine-induced structural plasticity in mesencephalic dopaminergic neurons via ERK and Akt pathways. J Neurochem 2012; 120: 765–778.

    Article  CAS  PubMed  Google Scholar 

  40. Collo G, Bono F, Cavalleri L, Plebani L, Mitola S, Merlo Pich E et al. Nicotine-induced structural plasticity in mesencephalic dopaminergic neurons is mediated by dopamine D3 receptors and Akt-mTORC1 signaling. Mol Pharm 2013; 83: 1176–1189.

    Article  CAS  Google Scholar 

  41. Lindefors N, Barati S, O’Connor WT . Differential effects of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in rat medial prefrontal cortex. Brain Res 1997; 759: 205–212.

    Article  CAS  PubMed  Google Scholar 

  42. Kegeles LS, Abi-Dargham A, Zea-Ponce Y, Rodenhiser-Hill J, Mann JJ, Van Heertum RL et al. Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia. Biol Psychiatry 2000; 48: 627–640.

    Article  CAS  PubMed  Google Scholar 

  43. Can A, Zanos P, Moaddel R, Kang HJ, Dossou KS, Wainer IW et al. Effects of ketamine and ketamine metabolites on evoked striatal dopamine release, dopamine receptors, and monoamine transporters. J Pharmacol Exp Ther 2016; 359: 159–170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Belujon P, Grace AA . Restoring mood balance in depression: ketamine reverses deficit in dopamine-dependent synaptic plasticity. Biol Psychiatry 2014; 76: 927–936.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Devine MJ, Ryten M, Vodicka P, Thomson AJ, Burdon T, Houlden H et al. Parkinson's disease induced pluripotent stem cells with triplication of the α-synuclein locus. Nat Commun 2011; 2: 440.

    Article  PubMed  Google Scholar 

  46. Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature 2011; 480: 547–551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Avior Y, Sagi I, Benvenisty N . Pluripotent stem cells in disease modelling and drug discovery. Nat Rev Mol Cell Biol 2016; 17: 170–182.

    Article  CAS  PubMed  Google Scholar 

  48. Accili D, Fishburn CS, Drago J, Steiner H, Lachowicz JE, Park B-H et al. A targeted mutation of the D3 dopamine receptor gene is associated with hyperactivity in mice. Proc Natl Acad Sci USA 1996; 93: 1945–1949.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Fischer G, Mutel V, Trube G, Malherbe P, Kew JN, Mohacsi E et al. Ro 25-6981, a highly potent and selective blocker of N-methyl-D-aspartate receptors containing the NR2B subunit. Characterization in vitro. J Pharmacol Exp Ther 1997; 283: 1285–1292.

    CAS  PubMed  Google Scholar 

  50. Arai AC, Kessler M, Rogers G, Lynch G . Effects of the potent ampakine CX614 on hippocampal and recombinant AMPA receptors: interactions with cyclothiazide and GYKI52466. Mol Pharmacol 2000; 58: 802–813.

    Article  CAS  PubMed  Google Scholar 

  51. Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 2016; 533: 481–486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chen L-W, Weib L-C, Langa B, Jua G, Chanc YS . Differential expression of AMPA receptor subunits in dopamine neurons of the rat brain: a double immunocytochemical study. Neuroscience 2001; 106: 149–160.

    Article  CAS  PubMed  Google Scholar 

  53. Chen W, Prithviraj R, Mahnke AH, McGloin KE, Tan JW, Gooch AK et al. AMPA glutamate receptor subunits 1 and 2 regulate dendrite complexity and spine motility in neurons of the developing neocortex. Neuroscience 2009; 159: 172–182.

    Article  CAS  PubMed  Google Scholar 

  54. Lauterborn JC, Palmer LC, Jia Y, Pham DT, Hou B, Wang W et al. Chronic ampakine treatments stimulate dendritic growth and promote learning in middle-aged rats. J Neurosci 2016; 36: 1636–1646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Reavill C, Taylor SG, Wood MD, Ashmeade T, Austin NE, Avenell KY et al. Pharmacological actions of a novel, high-affinity, and selective human dopamine D(3) receptor antagonist, SB277011-A. J Pharmacol Exp Ther 2000; 294: 1154–1165.

    CAS  PubMed  Google Scholar 

  56. Millan MJ, Gobert A, Newman-Tancredi A, Lejeune F, Cussac D, Rivet JM et al. S33084, a novel, potent, selective, and competitive antagonist at dopamine D(3)-receptors: I. Receptorial, electrophysiological and neurochemical profile compared with GR218,231 and L741,626. J Pharmacol Exp Ther 2000; 293: 1048–1062.

    CAS  PubMed  Google Scholar 

  57. Meador-Woodruff JH, Mansour A, Healy DJ, Kuehn R, Zhou QY, Bunzow JR et al. Comparison of the distributions of D1 and D2 dopamine receptor mRNAs in rat brain. Neuropsychopharmacol 1991; 5: 231–242.

    CAS  Google Scholar 

  58. Zhao X, Venkata SL, Moaddel R, Luckenbaugh DA, Brutsche NE, Ibrahim L et al. Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment-resistant bipolar depression. Br J Clin Pharmacol 2012; 74: 304–314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kumar V, Zhang M-X, Swank MW, Kunz J, Wu G-Y . Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. J Neurosci 2005; 25: 11288–11299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Murray F, Kennedy J, Hutson PH, Elliot J, Huscroft I, Mohnen K et al. Modulation of [3H]MK-801 binding to NMDA receptors in vivo and in vitro. Eur J Pharmacol 2000; 397: 263–270.

    Article  CAS  PubMed  Google Scholar 

  61. Suzuki K, Nosyreva E, Hunt KW, Kavalali ET, Monteggia LM . Effects of a ketamine metabolite on synaptic NMDAR function. Nature 2017; 546: E1–E3.

    Article  CAS  PubMed  Google Scholar 

  62. Lauterborn JC, Truong GS, Baudry M, Bi X, Lynch G, Gall CM . Chronic elevation of brain-derived neurotrophic factor by ampakines. J Pharmacol Exp Ther 2003; 307: 297–305.

    Article  CAS  PubMed  Google Scholar 

  63. Nations KR, Dogterom P, Bursi R, Schipper J, Greenwald S, Zraket D et al. Examination of Org 26576, an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: an exploratory, randomized, double-blind, placebo-controlled trial. J Psychopharmacol 2012; 26: 1525–1539.

    Article  CAS  PubMed  Google Scholar 

  64. Zweifel LS, Argilli E, Bonci A, Palmiter RD . Role of NMDA receptors in dopamine neurons for plasticity and addictive behaviors. Neuron 2008; 59: 486–496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Alme MN, Wibrand K, Dagestad G, Bramham CR . Chronic fluoxetine treatment induces brain region-specific upregulation of genes associated with BDNF induced long-term potentiation. Neural Plast 2007; 2007: 26496.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Björkholm C, Monteggia LM . BDNF - a key transducer of antidepressant effects. Neuropharmacology 2016; 102: 72–79.

    Article  PubMed  Google Scholar 

  67. Miczek KA, Nikulina EM, Shimamoto A, Covington HE 3rd . Escalated or suppressed cocaine reward, tegmental BDNF, and accumbal dopamine caused by episodic versus continuous social stress in rats. J Neurosci 2011; 31: 9848–9857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM . Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav 1997; 56: 131–137.

    Article  CAS  PubMed  Google Scholar 

  69. Molteni R, Calabrese F, Bedogni F, Tongiorgi E, Fumagalli F, Racagni G et al. Chronic treatment with fluoxetine up-regulates cellular BDNF mRNA expression in rat dopaminergic regions. Int J Neuropsychopharmacol 2006; 9: 307–317.

    Article  CAS  PubMed  Google Scholar 

  70. Wook Koo J, Labonté B, Engmann O, Calipari ES, Juarez B, Lorsch Z et al. Essential role of mesolimbic brain-derived neurotrophic factor in chronic social stress-induced depressive behaviors. Biol Psychiatry 2016; 80: 469–478.

    Article  PubMed  Google Scholar 

  71. Van Kampen JM, Eckman CB . Dopamine D3 receptor agonist delivery to a model of Parkinson's disase restores the nigrostriatal pathway and improves locomotor behavior. J Neurosci 2006; 26: 7272–7280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Mueller D, Chapman CA, Stewart J . Amphetamine induces dendritic growth in ventral tegmental area dopaminergic neurons in vivo via basic fibroblast grow factor. Neuroscience 2006; 137: 727–735.

    Article  CAS  PubMed  Google Scholar 

  73. Razgado-Hernandez LF, Espadas-Alvarez AJ, Reyna-Velazquez P, Sierra-Sanchez A, Anaya-Martinez V, Jimenez-Estrada I et al. The transfection of BDNF to dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation, dendritic spines and motor behavior in an aged rat model of Parkinson's disease. PLoS ONE 2015; 10: e0117391.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Searle G, Beaver JD, Comley RA, Bani M, Tziortzi A, Slifstein M et al. Imaging dopamine D3 receptors in the human brain with positron emission tomography, [11C]PHNO, and a selective D3 receptor antagonist. Biol Psychiatry 2010; 68: 392–399.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Cristina Mora for PCR analysis, Florent Meunier and Marie Hideux for high performance liquid chromatography and mass spectrometry of ketamine in culture media, Marzia Di Chio for technical assistance, Verdon Taylor for critical comments on the manuscript and figures. Research was supported by: Grant from ex-60%, University of Brescia to GC and by MIUR ex-60% research funds to CC.

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Authors and Affiliations

  1. Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy

    L Cavalleri, P F Spano & G Collo

  2. CNS Therapeutic Area Unit, Takeda Development Center Europe, London, UK

    E Merlo Pich

  3. Centre for Therapeutic Innovation-CNS, Institut de Recherches Servier, Croissy-Sur-Seine, France

    M J Millan

  4. Department Public Health & Community Medicine, University of Verona, Verona, Italy

    C Chiamulera

  5. MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, University of Edinburgh, Edinburgh, UK

    T Kunath

  6. Department of Biomedicine, University of Basel, Basel, Switzerland

    G Collo

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  1. L Cavalleri
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Correspondence to G Collo.

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EMP is full time employee at Takeda Pharmaceuticals; MJM is full time employee at Institute de Recherches Servier. The remaining authors declare no conflict of interest.

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Cavalleri, L., Merlo Pich, E., Millan, M. et al. Ketamine enhances structural plasticity in mouse mesencephalic and human iPSC-derived dopaminergic neurons via AMPAR-driven BDNF and mTOR signaling. Mol Psychiatry 23, 812–823 (2018). https://doi.org/10.1038/mp.2017.241

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