Chronic lithium treatment elicits its antimanic effects via BDNF-TrkB dependent synaptic downscaling
- UT Southwestern Medical Center, United States
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.
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Author details
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).
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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Chronic lithium treatment elicits its antimanic effects via BDNF-TrkB dependent synaptic downscaling
eLife 6:e25480.
https://doi.org/10.7554/eLife.25480
