10 Sep 1998

Glutamate is a neurotransmitter that is toxic when too much of it is released by excessive neuronal activity or by brain injury. Some researchers have also proposed that glutamate toxicity drives the neurodegeneration seen in Alzheimer's disease. (See John Olney's seminar.) It has long been assumed that glutamate does its damage by allowing excessive levels of calcium to build up in the cell's cytoplasm, but findings published in this month's Nature Neuroscience indicate that it is the accumulation of calcium in the mitochondria, not the cytoplasm, that triggers neuronal death. "We discovered that neurons can tolerate 20 times more calcium than what was formerly believed to be lethal, as long as this calcium doesn't get inside mitochondria," said Amy Stout, a postdoctoral research in Ian Reynold's laboratory at the University of Pittsburgh School of Medicine. In their studies, Stout and her coworkers exposed cultured neurons from the forebrains of rats to varying concentrations of calcium. In some cases, they also exposed the cells to chemicals that block the uptake of calcium by mitochondria. Cells that received high levels of calcium but no mitochondrial blockers died. Cells that were exposed to high calcium concentrations and mitochondrial calcium blockers survived. Mitochondria work to remove excess calcium, but having to do so constantly may sap them of energy and also spur the formation of destructive free radicals. This research suggests that drugs designed to target calcium channels on mitochondria could intervene effectively in glutamate neurotoxicity.—June Kinoshita