Article

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

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.
Science (Impact Factor: 31.48). 08/2010; 329(5994):959-64. DOI: 10.1126/science.1190287
Source: PubMed

ABSTRACT 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.

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