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.
Highlights
Lithium was initially reported for treatment as a mood stabilizer over 60 years ago (Cade, 1949) and is still widely used for the treatment of Bipolar Disorder (Mitchell, 2013; Poolsup et al, 2000; Vieta and Valentı, 2013)
Using Q-PCR targeted to the coding exon of Bdnf, we found lithium treated mice had a significant increase in Bdnf mRNA expression (Figure 1D)
We found a significant increase in brainderived neurotrophic factor (BDNF) protein expression (Figure 1E) in lithium treated mice relative to CTL mice
Summary
Lithium was initially reported for treatment as a mood stabilizer over 60 years ago (Cade, 1949) and is still widely used for the treatment of Bipolar Disorder (Mitchell, 2013; Poolsup et al, 2000; Vieta and Valentı, 2013). BDNF and aberrant signaling through its high affinity receptor tropomyosin receptor kinase B (TrkB) have been proposed to underlie both the pathophysiology and treatment of bipolar disorder (Autry and Monteggia, 2012; Malhi et al, 2013; Scola and Andreazza, 2015). Previous work has shown that patients with bipolar disorder have decreased peripheral BDNF mRNA in blood lymphocytes and monocytes in comparison to healthy controls (D’Addario et al, 2012). Both manic and depressive states in patients with bipolar disorder have been associated with significantly decreased BDNF blood serum levels compared to patients in euthymic states and healthy controls
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