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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. 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

Spontaneous glutamate release-driven NMDA receptor activity exerts a strong influence on synaptic homeostasis. However, the properties of Ca2+ signals that mediate this effect remain unclear. Here, using hippocampal neurons labeled with the fluorescent Ca2+ probes Fluo-4 or GCAMP5, we visualized action potential-independent Ca2+ transients in dendritic regions adjacent to fluorescently labeled presynaptic boutons in physiological levels of extracellular Mg2+. These Ca2+ transients required NMDA receptor activity, and their propensity correlated with acute or genetically induced changes in spontaneous neurotransmitter release. In contrast, they were insensitive to blockers of AMPA receptors, L-type voltage-gated Ca2+ channels, or group I mGluRs. However, inhibition of Ca2+-induced Ca2+ release suppressed these transients and elicited synaptic scaling, a process which required protein translation and eukaryotic elongation factor-2 kinase activity. These results support a critical role for Ca2+-induced Ca2+ release in amplifying NMDA receptor-driven Ca2+ signals at rest for the maintenance of synaptic homeostasis. DOI: http://dx.doi.org/10.7554/eLife.09262.001, eLife digest Learning and memory is thought to rely on changes in the strength of the connections between nerve cells. When an electrical impulse travelling through a nerve cell reaches one of these connections (called a synapse), it causes the cell to release chemical transmitter molecules. These bind to receptors on the cell on the other side of the synapse. This starts a series of events that ultimately leads to new receptors being inserted into the membrane of this second cell, which strengthens the connection between the two cells. The receptors involved in this process belong to two groups, called AMPA and NMDA receptors. Both groups are ion channels that regulate the flow of charged particles from one side of a cell's membrane to the other. In resting nerve cells, NMDA receptors are partially blocked by magnesium ions. However, the binding of the transmitter molecules to AMPA receptors causes these receptors to open and allow positively charged sodium ions into the cell. This changes the electrical charge across the cell membrane, which displaces the magnesium ions from the NMDA receptors so that they too open. Calcium ions then enter the cell through the NMDA receptors and activate a signaling cascade that leads to the production of new AMPA receptors. Nerve cells also release transmitter molecules in the absence of electrical impulses, and evidence suggests that individual cells can use this ‘spontaneous transmitter release’ to adjust the strength of their synapses. When these spontaneous release levels are high, AMPA receptors are removed from the membrane of the nerve after the synapse to make it less sensitive to the transmitter molecules. Conversely, when spontaneous release levels are low, additional AMPA receptors are added to the membrane to increase the sensitivity. Reese and Kavalali have now identified the mechanism behind this process by showing that spontaneously released transmitter molecules cause small amounts of calcium to enter the second nerve cell through NMDA receptors, even when these receptors are blocked by magnesium ions. This trickle of calcium triggers the release of more calcium from stores inside the cell, which amplifies the signal. The ultimate effect of the flow of calcium into the cell is to block the production of AMPA receptors, and ensure that the synapse does not become any stronger. As confirmation of this mechanism, Reese and Kavalali showed that simulating low levels of spontaneous activity by blocking the so-called ‘calcium-induced calcium release’ has the opposite effect. This led to more AMPA receptors being produced and stronger synapses. Taken together these findings indicate that spontaneous transmitter release exerts an outsized influence on communication between neurons by maintaining adequate levels of AMPA receptors via these ‘amplified’ calcium signals. DOI: http://dx.doi.org/10.7554/eLife.09262.002