Stimulating clue hints how lithium works.

Some 50 years ago, Australian physician John Cade observed the calming effect that lithium had on small animals. After testing the safety of lithium on himself, Cade ventured to try it on people suffering from the wild mood swings of manic depression.

Millions of prescriptions later, lithium remains the most popular choice for treating manic depression, although scientists do not understand how it quells mania or relieves depression. "It's still a mystery," says De-Maw Chuang of the National Institute of Mental Health in Bethesda, Md.

Now, there's a new clue to this riddle. Chuang and his colleagues have found that lithium protects brain cells from being stimulated to death by glutamate, one of the many chemicals that transmit messages in the brain.

The new data suggest that lithium may calm overexcited areas of the brain or, more provocatively, preserve the life of brain cells whose presence guards against manic depression.

This finding "potentially contributes a lot to the field," says Husseini K. Manji of Wayne State University in Detroit. "If we could figure out how lithium works, we could theoretically come up with better drugs and perhaps understand what's going on in manic depression."

Chuang and his colleagues tested the response of various types of rat brain cells to glutamate. Many normal cells and cells soaked in lithium for only a day died from a form of suicide that often results when this neurotransmitter overstimulates a brain cell.

Yet rat brain cells soaked in lithium for about a week committed suicide much more rarely when exposed to glutamate, Chuang's group reports in the March 3 Proceedings of the National Academy of Sciences. The effect was seen in cells from several brain regions.

The delay in protection is particularly striking, notes Manji, since a hallmark of lithium therapy is that it can take a week or longer to benefit people. Consequently, scientists have been looking for the long-term actions of lithium on brain cells.

Chuang's team also examined the role of the NMDA receptor, the cell surface protein that glutamate binds to when it excites a cell. While cells soaked in lithium for a week had as many NMDA receptors as untreated cells, the treated cells responded differently.

Normally, activation of the NMDA receptor by glutamate triggers an influx of calcium ions, setting off a signaling cascade inside cells. However, cells soaked in lithium for a week let in far less calcium when exposed to glutamate.

In people with manic depression, lithium may correct a dysfunction of the NMDA receptor by limiting calcium influx, speculates Chuang.

Both Chuang and Manji also note that a small body of evidence suggests that people with mania or depression may lose brain cells. Lithium may thwart that cell death, they say. Indeed, Manji has some evidence that lithium-treated cells eventually begin to overproduce a protein that stymies the cell's internal suicide program.

If lithium protects brain cells from death by glutamate overstimulation, it may have uses beyond manic depression. This form of cell death occurs in strokes and in Alzheimer's, Parkinson's, and Huntington's diseases. Chuang is investigating whether lithium protects mice from similar neurodegenerative illnesses.