GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine

  1. Oliver H Miller
  2. Lingling Yang
  3. Chih-Chieh Wang
  4. Elizabeth A Hargroder
  5. Yihui Zhang
  6. Eric Delpire
  7. Benjamin J Hall  Is a corresponding author
  1. Tulane University, United States
  2. Vanderbilt University Medical Center, United States

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 2B∆Ctx 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.

Article and author information

Author details

  1. Oliver H Miller

    Tulane University, New Orleans, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Lingling Yang

    Tulane University, New Orleans, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Chih-Chieh Wang

    Tulane University, New Orleans, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Elizabeth A Hargroder

    Tulane University, New Orleans, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yihui Zhang

    Tulane University, New Orleans, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Eric Delpire

    Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Benjamin J Hall

    Tulane University, New Orleans, United States
    For correspondence
    benhall@tulane.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of Tulane University (#0363R and 0364R).

Reviewing Editor

  1. Gary L Westbrook, Vollum Institute, United States

Publication history

  1. Received: June 4, 2014
  2. Accepted: October 22, 2014
  3. Accepted Manuscript published: October 23, 2014 (version 1)
  4. Version of Record published: December 12, 2014 (version 2)

Copyright

© 2014, Miller et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Oliver H Miller
  2. Lingling Yang
  3. Chih-Chieh Wang
  4. Elizabeth A Hargroder
  5. Yihui Zhang
  6. Eric Delpire
  7. Benjamin J Hall
(2014)
GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine
eLife 3:e03581.
https://doi.org/10.7554/eLife.03581

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