mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine [a glut...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2010-08, Vol.329 (5994), p.959-964
Main Authors: Li, Nanxin, Lee, Boyoung, Liu, Rong-Jian, Banasr, Mounira, Dwyer, Jason M., Iwata, Masaaki, Li, Xiao-Yuan, Aghajanian, George, Duman, Ronald S.
Format: Article
Language:English
Subjects:
Actins
Animals
Antidepressants
Antidepressive Agents - pharmacokinetics
Antidepressive Agents - pharmacology
Biological and medical sciences
Cell lines
Dendritic Spines - drug effects
Dendritic Spines - metabolism
Depression - drug therapy
Depression - metabolism
Female animals
General pharmacology
Integrins
Intracellular Signaling Peptides and Proteins - agonists
Ketamine - pharmacokinetics
Ketamine - pharmacology
Male
Mating behavior
Matrix materials
Medical sciences
Miscellaneous
Neurons
Neurons - drug effects
Neurons - metabolism
Neuropeptides - biosynthesis
Neuropeptides - metabolism
Pharmacology. Drug treatments
Phenols - pharmacology
Piperidines - pharmacology
Protein Biosynthesis - drug effects
Protein-Serine-Threonine Kinases
Rats
Rats, Sprague-Dawley
Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors
Signal Transduction - drug effects
Sirolimus - pharmacology
Synapses
Synapses - drug effects
Synapses - metabolism
Synapsins
Time Factors
TOR Serine-Threonine Kinases
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Description
Summary:The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine [a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist] have not been identified. We observed that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1190287