부산대학교 도서관

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 [alpha]-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. DOI: http://dx.doi.org/10.7554/eLife.25480.001 eLife digest Nerve cells, or neurons, communicate with each other by releasing chemical messengers that bind to and activate receptor proteins on the surface of the other cells. The chemicals affect the connections between neurons, and many diseases -- including bipolar disorder -- are related to there being too much or too little of these chemicals in the brain. Patients with bipolar disorder experience periods of both depression and mania. During a manic episode, affected individuals typically feel elated and have more energy than usual despite needing less sleep, but also can also be irritable and impulsive. The exact cause of bipolar disorder is unknown. Patients with bipolar disorder often have low levels of a protein called brain-derived neurotrophic factor, or BDNF for short, which plays an essential role in keeping the brain healthy, and may also regulate the connections between neurons. One of the main treatments for bipolar disorder, a mood stabilizer called lithium, has also been linked to BDNF in previous studies; however, the details of the interaction were not clear. Gideons et al. studied how lithium works by feeding mice food pellets that contained lithium. After a few weeks, the mice had concentrations of lithium in their blood comparable to those of people taking the drug, as well as increased levels of BDNF in the brain. Gideons et al. then examined if BDNF was needed for the lithium's ability to treat manic episodes. Mice exposed to another drug, amphetamine, normally move around a lot, mimicking the increased energy of someone with mania. As expected, feeding normal mice lithium blocked this effect of amphetamine, but feeding lithium to mutant mice that lack BDNF did not. This indicates that BDNF is indeed needed for the antimanic effect of lithium. Further experiments showed that BDNF is not needed for lithium's antidepressant effect. By studying the animals' brains, Gideons et al. went on to show that the lithium-fed mice had weaker connections between their neurons than mice that had eaten standard food. In the lithium-fed mice, many of the receptor proteins had been reabsorbed back into the neurons, lowering the ability of neurons to communicate with one another. This process depended on BDNF, suggesting that this protein is essential for lithium to suppress the connections between neurons. Taken together, these results reveal that the effects of lithium on both an animal's brain and its behavior rely on BDNF. This knowledge should make it easier to develop new strategies and identifying new molecularly specific targets for treating bipolar disorder as well as other neuropsychiatric diseases. DOI: http://dx.doi.org/10.7554/eLife.25480.002
Byline: Erinn S Gideons, Pei-Yi Lin, Melissa Mahgoub, Ege T Kavalali, Lisa M Monteggia Introduction Lithium was initially reported for treatment as a mood stabilizer over 60 years ago (Cade, [...]