In experiments with mice, scientists from Johns Hopkins' Institute for Cell Engineering have discovered the steps required to integrate new neurons into the brain's existing operations.
For more than a century, scientists thought the adult brain could only lose nerve cells, not gain them, but in fact, new neurons do form during adulthood in all mammals, including humans, and become a working part of the adult brain in mice at the very least.
In the first study to show how these "baby" neurons are integrated into the brain's existing networks, the Johns Hopkins researchers show that a brain chemical called GABA readies baby neurons to make connections to old ones. The discovery is described in the Dec. 11 advance online section of Nature.
"GABA is important during fetal development, but most scientists thought it would have the same role it has with adult neurons, which is to inhibit the cells' signals," says Hongjun Song, Ph.D., an assistant professor in the Neuroregeneration and Repair Program within ICE. "We've shown that GABA instead excites new neurons and that this is the first step toward their integration into the adult brain."
Song added that their discovery might help efforts to increase neuron regeneration in the brain or to make transplanted stem cells form connections more efficiently.
The researchers, including postdoctoral fellows Shaoyu Ge and Eyleen Goh, discovered that a constant flood of GABA is required as a first step. Next, the new neuron receives specific connections that communicate using GABA, which shifts the constant barrage of GABA in step one to a pulsed exposure. The third and final step occurs when the new neuron receives connections that communicate via another chemical, the critical excitatory messenger glutamate.
In the adult brain, glutamate is the most prevalent excitatory chemical, and GABA is a major inhibitory chemical. But it turns out that new neurons are excited by GABA, whether they are in the fetal brain or the adult brain, says Song.
"The steps of integration essentially shift the neuron from being a developing neuron to being an adult neuron. Initially it's excited by the flood of GABA, but by the time it's fully integrated, the neuron will respond to GABA and glutamate like other adult neurons," he says.
The researchers' experiments were done on a part of the mouse brain called the dentate gyrus, which is thought to be involved in memory and spatial reasoning, or navigation. It is one of the few parts of the brain where new neurons form throughout life and are integrated into the existing network of cells.
The researchers also figured out why the mouse's new neurons were excited by GABA -- they have greater amounts of chloride ions, making for a different chemical environment. By the time they are fully integrated, their chloride levels have dropped and are similar to other adult neurons.
In the mouse experiments, Goh used a technique to alter the genetics of single cells in order to change new neurons' ability to accumulate chloride ions (and thus to manipulate their response to GABA) and to make them glow with a green protein to ease their identification in the adult brain. Ge measured the electrical output of the neurons to establish whether they had become connected to other neurons.
"Getting new neurons to form connections in other parts of the brain may be helped through the same steps that naturally lead to integration in the dentate gyrus," says Song.
Among the most likely targets for regeneration or replacement efforts are the dopamine-producing neurons that die in Parkinson's disease, muscle-controlling nerves that succumb in diseases like muscular dystrophy and amyotrophic lateral sclerosis, or nerves that are damaged by trauma or injury. In none of these systems are new neurons formed or integrated to any great extent naturally.
Authors on the report are Ge, Goh, Song, Kurt Sailor, Yasuji Kitabatake and Guo-Li Ming, all of Johns Hopkins' Institute for Cell Engineering and the departments of neurology and neuroscience at the Johns Hopkins School of Medicine. The researchers were funded by the National Institutes of Health, The Klingenstein Fellowship Awards in the Neurosciences, the Whitehall Foundation and the Robert Packard Center for ALS Research at Johns Hopkins.
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