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Chronic lithium treatment elicits its antimanic effects via BDNF-TrkB dependent synaptic downscaling

  1. Erinn S Gideons
  2. Pei-Yi Lin
  3. Melissa Mahgoub
  4. Ege T Kavalali
  5. Lisa M Monteggia Is a corresponding author
  1. UT Southwestern Medical Center, United States
Research Article
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Cite as: eLife 2017;6:e25480 doi: 10.7554/eLife.25480

Abstract

Lithium is widely used as a treatment for Bipolar Disorder although the molecular mechanisms that underlie its therapeutic effects are under debate. In this study, we show brain-derived neurotrophic factor (BDNF) is required for the antimanic-like effects of lithium but not the antidepressant-like effects in mice. We performed whole cell patch clamp recordings of hippocampal neurons to determine the impact of lithium on synaptic transmission that may underlie the behavioral effects. Lithium produced a significant decrease in α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated miniature excitatory postsynaptic current (mEPSC) amplitudes due to postsynaptic homeostatic plasticity that was dependent on BDNF and its receptor tropomyosin receptor kinase B (TrkB). The decrease in AMPAR function was due to reduced surface expression of GluA1 subunits through dynamin-dependent endocytosis. Collectively, these findings demonstrate a requirement for BDNF in the antimanic action of lithium and identify enhanced dynamin-dependent endocytosis of AMPARs as a potential mechanism underlying the therapeutic effects of lithium.

Article and author information

Author details

  1. Erinn S Gideons

    1. Department of Neuroscience, UT Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Pei-Yi Lin

    1. Department of Neuroscience, UT Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Melissa Mahgoub

    1. Department of Neuroscience, UT Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ege T Kavalali

    1. Department of Neuroscience, UT Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0003-1777-227X
  5. Lisa M Monteggia

    1. Department of Neuroscience, UT Southwestern Medical Center, Dallas, United States
    For correspondence
    1. lisa.monteggia@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0003-0018-501X

Funding

National Institute of Mental Health (MH070727 MH066198)

  • Ege T Kavalali
  • Lisa M Monteggia

Brain and Behavior Research Foundation (Distinguished Investigator Award)

  • Ege T Kavalali
  • Lisa M Monteggia

International Mental Health Research Organization (Research Award)

  • Lisa M Monteggia

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal protocols were approved by the Institutional Care and Use Committee at UT Southwestern Medical Center (UTSW APN# 2017-101831G).

Reviewing Editor

  1. Inna Slutsky, Reviewing Editor, Tel Aviv University, Israel

Publication history

  1. Received: January 26, 2017
  2. Accepted: June 7, 2017
  3. Accepted Manuscript published: June 16, 2017 (version 1)

Copyright

© 2017, Gideons 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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