Chronic Lithium Treatment Elicits Its Antimanic Effects Via BDNF-TrkB Dependent Synaptic Downscaling

Overview

Journal Elife

Specialty Biology

Date 2017 Jun 17

PMID 28621662

Citations 23

Authors

Erinn S Gideons

Pei-Yi Lin

Melissa Mahgoub

Ege T Kavalali

Lisa M Monteggia

Affiliations

Soon will be listed here.

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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References

Jornada L, Moretti M, Valvassori S, Ferreira C, Padilha P, Arent C . Effects of mood stabilizers on hippocampus and amygdala BDNF levels in an animal model of mania induced by ouabain. J Psychiatr Res. 2009; 44(8):506-10. DOI: 10.1016/j.jpsychires.2009.11.002. View

Duman R, Monteggia L . A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006; 59(12):1116-27. DOI: 10.1016/j.biopsych.2006.02.013. View

Wei J, Liu W, Yan Z . Regulation of AMPA receptor trafficking and function by glycogen synthase kinase 3. J Biol Chem. 2010; 285(34):26369-76. PMC: 2924064. DOI: 10.1074/jbc.M110.121376. View

Nakata H, Nakamura S . Brain-derived neurotrophic factor regulates AMPA receptor trafficking to post-synaptic densities via IP3R and TRPC calcium signaling. FEBS Lett. 2007; 581(10):2047-54. DOI: 10.1016/j.febslet.2007.04.041. View

Smith M, Makino S, Kvetnansky R, Post R . Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci. 1995; 15(3 Pt 1):1768-77. PMC: 6578156. View

Eastwood S, Harrison P . Markers of glutamate synaptic transmission and plasticity are increased in the anterior cingulate cortex in bipolar disorder. Biol Psychiatry. 2010; 67(11):1010-6. PMC: 2868790. DOI: 10.1016/j.biopsych.2009.12.004. View

Tunca Z, Ozerdem A, Ceylan D, Yalcin Y, Can G, Resmi H . Alterations in BDNF (brain derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) serum levels in bipolar disorder: The role of lithium. J Affect Disord. 2014; 166:193-200. DOI: 10.1016/j.jad.2014.05.012. View

Fernandes B, Molendijk M, Kohler C, Soares J, Leite C, Machado-Vieira R . Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies. BMC Med. 2015; 13:289. PMC: 4666054. DOI: 10.1186/s12916-015-0529-7. View

Nosyreva E, Szabla K, Autry A, Ryazanov A, Monteggia L, Kavalali E . Acute suppression of spontaneous neurotransmission drives synaptic potentiation. J Neurosci. 2013; 33(16):6990-7002. PMC: 3661220. DOI: 10.1523/JNEUROSCI.4998-12.2013. View

10.

Hashimoto K, Sawa A, Iyo M . Increased levels of glutamate in brains from patients with mood disorders. Biol Psychiatry. 2007; 62(11):1310-6. DOI: 10.1016/j.biopsych.2007.03.017. View

11.

Luikart B, Nef S, Virmani T, Lush M, Liu Y, Kavalali E . TrkB has a cell-autonomous role in the establishment of hippocampal Schaffer collateral synapses. J Neurosci. 2005; 25(15):3774-86. PMC: 6724922. DOI: 10.1523/JNEUROSCI.0041-05.2005. View

12.

Malhi G, Outhred T . Therapeutic Mechanisms of Lithium in Bipolar Disorder: Recent Advances and Current Understanding. CNS Drugs. 2016; 30(10):931-49. DOI: 10.1007/s40263-016-0380-1. View

13.

DAddario C, DellOsso B, Palazzo M, Benatti B, Lietti L, Cattaneo E . Selective DNA methylation of BDNF promoter in bipolar disorder: differences among patients with BDI and BDII. Neuropsychopharmacology. 2012; 37(7):1647-55. PMC: 3358733. DOI: 10.1038/npp.2012.10. View

14.

Ferguson S, Brasnjo G, Hayashi M, Wolfel M, Collesi C, Giovedi S . A selective activity-dependent requirement for dynamin 1 in synaptic vesicle endocytosis. Science. 2007; 316(5824):570-4. DOI: 10.1126/science.1140621. View

15.

Vieta E, Valenti M . Pharmacological management of bipolar depression: acute treatment, maintenance, and prophylaxis. CNS Drugs. 2013; 27(7):515-29. DOI: 10.1007/s40263-013-0073-y. View

16.

Leslie K, Nelson S, Turrigiano G . Postsynaptic depolarization scales quantal amplitude in cortical pyramidal neurons. J Neurosci. 2001; 21(19):RC170. PMC: 6762907. View

17.

Knable M, Barci B, Webster M, Meador-Woodruff J, Torrey E . Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium. Mol Psychiatry. 2004; 9(6):609-20, 544. DOI: 10.1038/sj.mp.4001471. View

18.

Rios M, Fan G, Fekete C, Kelly J, Bates B, Kuehn R . Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol Endocrinol. 2001; 15(10):1748-57. DOI: 10.1210/mend.15.10.0706. View

19.

Adachi M, Barrot M, Autry A, Theobald D, Monteggia L . Selective loss of brain-derived neurotrophic factor in the dentate gyrus attenuates antidepressant efficacy. Biol Psychiatry. 2007; 63(7):642-9. PMC: 2352150. DOI: 10.1016/j.biopsych.2007.09.019. View

20.

CADE J . Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949; 2(10):349-52. DOI: 10.1080/j.1440-1614.1999.06241.x. View