Brain cells may have a natural ability to resist damage from strokes and other neurological disorders, according to new results from researchers at Washington University School of Medicine in St. Louis.
Scientists found neurons exposed to conditions similar to those that occur in a stroke could suppress the release of glutamate, a chemical that floods the brain during strokes. Glutamate normally transmits messages from one brain cell to another, but overexposure to glutamate during strokes and other disorders also promotes a chain reaction that damages or kills nerve cells, literally exciting them to death.
A better understanding of this process could help researchers improve treatments for stroke, according to senior investigator Steven J. Mennerick, Ph.D., assistant professor of psychiatry.
First author for the paper, published in the May 13 issue of the journal Neuron, was postdoctoral fellow Krista Moulder, Ph.D.
Neurologists have known for decades that neurons can adjust the “volume” of their communications with each other, making it easier or harder for them to transmit a signal across the synapse — the gap across which nerve cells communicate. These volume adjustments, known as plasticity, are thought to be involved in learning and memory.
There have been hints that a mechanism similar to plasticity also might help nerve cells avoid being overexposed to glutamate during a stroke, but Mennerick’s new results are the most direct and detailed observations yet of a sending cell settling down to avoid killing an overexcited receiving cell.
To simulate the conditions that occur during a stroke, Mennerick increased the levels of potassium in a solution surrounding cultured rat brain cells and rat brain slices. High potassium levels are prominent during stroke and cause brain cells to lose the electrical polarization along their outer membranes. This electrical change starts a chain reaction that causes cell damage and death.
Glutamate, which excites nerve cells and increases the likelihood that they will pass on signals, can both be released by this chain reaction and increase its intensity. However, when researchers studied the synaptic activity of cells exposed to higher potassium levels, they found that glutamate transmission somehow had been suppressed.
“Structurally the synapses are still there, but functionally they disappear,” says Mennerick. “Glutamate comes to the synapse of sending neurons in little spheres known as vesicles, and we can see the vesicles are still coming to the staging area where they are prepared for release. But somehow the sending cell is becoming much more reluctant to actually allow the glutamate into the synapse.”
Mennerick notes that during a stroke other processes probably overpower this protective property.
“The mechanisms we studied may help limit the neuronal death during stroke, but there certainly are other mechanisms at work during a stroke that will work to counteract these protective mechanisms and may overwhelm them in many circumstances,” he says.
The same experimental conditions had no effect on a sending nerve cell that uses GABA, a neurotransmitter that inhibits nerve cell activity and is not associated with stroke damage, further suggesting that the glutamate effect might be an attempt to limit damage from overexcitement.
When researchers restored normal potassium levels around the glutamate cells, normal glutamate release resumed in one to four hours.
Mennerick plans follow-up studies that will include electron microscopy of suppressed glutamate synapses and studies of the phenomenon’s potential connections to priming proteins, which help prepare vesicles for use at the synapse.
Moulder KL, Meeks JP, Shute AA, Hamilton CK, Erausquin G, Mennerick S. Plastic elimination of functional glutamate release sites by depolarization. Neuron vol. 42, May 13, 2004.
Funding from the National Institute of Neurological Disorders and Stroke and the National Institute on Alcohol Abuse and Alcoholism.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked second in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.