Possible explanation for lithium efficacy

Pharmacological success as a mood stabilizer poorly understood

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CAMBRIDGE, Mass.—Lithium was first discovered as a chemical element in 1817 and, along with electroconvulsive therapy, has come to be known as one of the single most effective treatments in psychiatry. It is used to treat mental illnesses such as bipolar disorder, depression and schizophrenia, as well as eating disorders such as anorexia and bulimia.
Lithium is an element present in trace amounts in virtually all rocks that interacts with many proteins and other molecules in the brain, so it has been difficult for scientists to determine which of these interactions produce mood stabilization. With proper dosage and medical monitoring for blood levels, side effects are easily manageable, and many patients remain relatively symptom-free for decades. While the drug has a good success rate, particularly for patients with bipolar disorder, scientists are still unsure exactly how it achieves its beneficial effects.
“How lithium acts on the brain has been this great mystery of psychopharmacology,” Joshua Meisel, a Massachusetts Institute of Technology (MIT) postdoc and lead author of the study, said in a press release. “There are hypotheses, but nothing’s been proven.”
MIT biologists have now discovered a possible explanation for how lithium works. In a study of Caenorhabditis elegans (a worm species with a simple nervous system) and its microbial environment, the researchers identified a key protein that is inhibited by lithium, making the worms less active.
Previous research had established that a pair of neurons known as ASJ neurons are necessary for the worm’s avoidance of harmful bacteria and for reawakening from a starvation-induced hibernation state. Principal researchers and study authors Meisel and Dennis Kim, an associate professor of biology, discovered in a genetic screen for mutated genes that disrupt ASJ neurons that one of the genes implicated codes for a protein called BPNT1, which was already known to be inhibited by lithium. BPNT1 removes phosphate groups from a compound known as PAP, a process that is critical to maintaining normal cell function.
When the researchers knocked out the gene for BPNT1, they found that the ASJ neurons entered a dormant state and the worms could no longer execute either avoidance behavior or the dauer exit. They also found the same behavioral effects in worms treated with lithium.
The researchers’ findings suggest that lithium treatment silences activity in neurons that rely on BPNT1, which Meisel and Kim found intriguing because many human brain cells also depend on this protein. In humans, PAP, which BPNT1 degrades, is usually found in neurons that secrete dopamine, epinephrine or norepinephrine, which are all neurotransmitters that stimulate brain activity.
“We think that it’s perfectly reasonable to add BPNT1 onto the list of hypotheses for how lithium is affecting the brain,” Meisel says. “Silencing dopaminergic neurons, I would think, would make you less manic because of how dopamine affects the brain.” While Kim’s lab focuses on worms, the researchers hope that other labs will test the new hypothesis in other animals.
Theories abound about what accounts for lithium’s unparalleled success. Upon ingestion, lithium becomes widely distributed in the central nervous system and interacts with a number of neurotransmitters and receptors, decreasing norepinephrine release and increasing serotonin synthesis.
Previous hypotheses about lithium targets include an enzyme that produces inositol, a sugar alcohol involved in cell signaling, and an enzyme called GSK3, which inactivates other proteins. It has been thought to modulate glutamate levels, which are often elevated during mania episodes, by competing with magnesium for binding to the NMDA glutamate receptor, increasing the availability of glutamate in post-synaptic neurons. However, no studies have conclusively linked these targets to lithium’s effects on bipolar patients.
“Establishing that this [silencing of dopaminergic neurons] happens in C. elegans [worms], by no means does it prove how lithium works in humans, but it provides a very solid experimental foundation for exploring a hypothesis that lithium might have therapeutic effects in specific neurons through inhibition of BPNT1,” Kim emphasizes. “We hope that other groups that work on mammalian systems may be interested to explore this question further.”

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