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 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.
Li
Nanxin
N
Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508, USA.
Lee
Boyoung
B
Liu
Rong-Jian
RJ
Banasr
Mounira
M
Dwyer
Jason M
JM
Iwata
Masaaki
M
Li
Xiao-Yuan
XY
Aghajanian
George
G
Duman
Ronald S
RS
D000818:Animals; D000928:Antidepressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000819:agonists; D007649:Ketamine / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000096:biosynthesis* / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors
D000928:Antidepressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D010636:Phenols; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D007649:Ketamine; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus