mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists
Nanxin Li, Boyoung Lee, Rongjian Liu, Mounira Banasr, Jason M. Dwyer, Masaaki Iwata, Xiaoyuan Li, George K. Aghajanian, Ronald S. Duman
Science August 19, 2010 DOI: 10.1126/science.1190287 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational study Peer reviewed |
|---|---|
| Population | Rats |
| Intervention | Ketamine |
| Topics | Ketamine |
| Keywords | Antidepressant Prefrontal cortex Pi3k/akt/mtor pathway Hippocampus Nmda receptor Synapse Pharmacology Signal transduction Cell biology Cognition |
| Citations | 2,875 |
| Post-publication review | 1 comment on PubPeer (opens in new tab) · last active December 2022 |
| Key findings | Ketamine rapidly activates the mTOR pathway, leading to increased synaptic proteins and new spine synapses in the prefrontal cortex of rats, and blocking mTOR signaling prevents ketamine's synaptogenic and behavioral antidepressant effects. |
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.