GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine
Oliver H Miller, Ling-Ling Yang, Chih-Chieh Wang, Elizabeth A Hargroder, Yihui Zhang, E. Delpire, Benjamin J Hall
Elife October 23, 2014 DOI: 10.7554/elife.03581 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Basic science animal study Peer reviewed |
|---|---|
| Population | Mice with cortical neuron-specific deletion of GluN2B (2BΔCtx mice) |
| Intervention | Ketamine |
| Topics | Depression Esketamine Ketamine |
| Key points | Deleting GluN2B from cortical principal neurons mimicked and occluded ketamine's effects on depression-like behavior, excitatory synaptic transmission, mTOR activation, and synaptic protein synthesis. The authors propose that ambient glutamate acting on cortical GluN2B-containing NMDA receptors regulates excitatory synaptic strength in prefrontal cortex and sets basal depression-like behavior, providing a cellular model for ketamine's rapid antidepressant actions. |
Abstract
A single, low dose of the NMDA receptor antagonist ketamine produces rapid antidepressant actions in treatment-resistant depressed patients. Understanding the cellular mechanisms underlying this will lead to new therapies for treating major depression. NMDARs are heteromultimeric complexes formed through association of two GluN1 and two GluN2 subunits. We show that in vivo deletion of GluN2B, only from principal cortical neurons, mimics and occludes ketamine's actions on depression-like behavior and excitatory synaptic transmission. Furthermore, ketamine-induced increases in mTOR activation and synaptic protein synthesis were mimicked and occluded in 2BΔCtx mice. We show here that cortical GluN2B-containing NMDARs are uniquely activated by ambient glutamate to regulate levels of excitatory synaptic transmission. Together these data predict a novel cellular mechanism that explains ketamine's rapid antidepressant actions. In this model, basal glutamatergic neurotransmission sensed by cortical GluN2B-containing NMDARs regulates excitatory synaptic strength in PFC determining basal levels of depression-like behavior. DOI: http://dx.doi.org/10.7554/eLife.03581.001
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.
Citations in the library
Cited by 116
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
- Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine Journal of Neuroscience November 30, 2020
- Ketamine: NMDA Receptors and Beyond Journal of Neuroscience November 2, 2016
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Cites 10
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- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
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- Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology January 2012
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