PMID- 29158584
OWN - NLM
STAT- MEDLINE
DCOM- 20190404
LR  - 20220129
IS  - 1476-5578 (Electronic)
IS  - 1359-4184 (Linking)
VI  - 23
IP  - 4
DP  - 2018 Apr
TI  - Ketamine enhances structural plasticity in mouse mesencephalic and human 
      iPSC-derived dopaminergic neurons via AMPAR-driven BDNF and mTOR signaling.
PG  - 812-823
LID - 10.1038/mp.2017.241 [doi]
AB  - 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 
      alpha-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.
FAU - Cavalleri, L
AU  - Cavalleri L
AD  - Department of Molecular and Translational Medicine, University of Brescia, 
      Brescia, Italy.
FAU - Merlo Pich, E
AU  - Merlo Pich E
AD  - CNS Therapeutic Area Unit, Takeda Development Center Europe, London, UK.
FAU - Millan, M J
AU  - Millan MJ
AD  - Centre for Therapeutic Innovation-CNS, Institut de Recherches Servier, 
      Croissy-Sur-Seine, France.
FAU - Chiamulera, C
AU  - Chiamulera C
AD  - Department Public Health & Community Medicine, University of Verona, Verona, 
      Italy.
FAU - Kunath, T
AU  - Kunath T
AD  - MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, 
      University of Edinburgh, Edinburgh, UK.
FAU - Spano, P F
AU  - Spano PF
AD  - Department of Molecular and Translational Medicine, University of Brescia, 
      Brescia, Italy.
FAU - Collo, G
AU  - Collo G
AD  - Department of Molecular and Translational Medicine, University of Brescia, 
      Brescia, Italy.
AD  - Department of Biomedicine, University of Basel, Basel, Switzerland.
LA  - eng
GR  - F-0902/PUK_/Parkinson's UK/United Kingdom
GR  - K-1205/PUK_/Parkinson's UK/United Kingdom
GR  - MR/J012831/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20171121
PL  - England
TA  - Mol Psychiatry
JT  - Molecular psychiatry
JID - 9607835
RN  - 0 (Antidepressive Agents)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Receptors, AMPA)
RN  - 0 (Receptors, Dopamine D3)
RN  - 0 (Receptors, Glutamate)
RN  - 0 (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate 
      receptor, human)
RN  - 690G0D6V8H (Ketamine)
RN  - 77521-29-0 (alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Antidepressive Agents/pharmacology
MH  - Brain/metabolism
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Dopaminergic Neurons/*drug effects
MH  - Hippocampus/metabolism
MH  - Humans
MH  - Induced Pluripotent Stem Cells/drug effects
MH  - Ketamine/*metabolism/pharmacology
MH  - Mesencephalon/*drug effects
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Neuronal Plasticity/*drug effects
MH  - Receptors, AMPA/drug effects/metabolism
MH  - Receptors, Dopamine D3/metabolism
MH  - Receptors, Glutamate/drug effects
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism
EDAT- 2017/11/22 06:00
MHDA- 2019/04/05 06:00
CRDT- 2017/11/22 06:00
PHST- 2016/07/04 00:00 [received]
PHST- 2017/08/06 00:00 [revised]
PHST- 2017/08/17 00:00 [accepted]
PHST- 2017/11/22 06:00 [pubmed]
PHST- 2019/04/05 06:00 [medline]
PHST- 2017/11/22 06:00 [entrez]
AID - mp2017241 [pii]
AID - 10.1038/mp.2017.241 [doi]
PST - ppublish
SO  - Mol Psychiatry. 2018 Apr;23(4):812-823. doi: 10.1038/mp.2017.241. Epub 2017 Nov 
      21.