Nov. 2, 2004 University of California, San Diego neurobiologists have discovered a chemical responsible for the bursts of electrical activity in the brain that guide the development of the visual system, a finding that may bring rewiring of damaged visual circuits closer to reality.
The scientists, who presented their evidence at a session of the annual Society for Neuroscience meeting in San Diego, said their discovery could also lead to a better understanding of birth defects in children born to mothers taking epilepsy medication.
Scientists have long recognized that spontaneous neural activity is needed for the normal development of the visual circuits in the brain, but how this activity is created is not well understood. UCSD researchers Marla Feller and Chih-Tien Wang detailed at the meeting their evidence that the chemical messenger adenosine controls the timing of these bursts of electrical activity. Knowing what triggers these waves of activity could make it possible to recreate them for therapeutic purposes, they said, and may shed light on disorders caused by their disruption.
“The waves of neural activity in the developing visual system have a remarkably stereotyped temporal pattern,” said Feller, an assistant professor of biology who led the study. “We show that the neurotransmitter adenosine may control this pattern by altering the excitability of cells in the retina. Ultimately findings that help us understand the mechanism that generates this spontaneous activity might make it possible to recreate it later in life; for example, to coax regenerated nerve cells to reconnect appropriately after an injury.”
“Another possible application of inducing patterned retinal activity in adult circuits is to set up the wiring in people who have been blinded since birth but then have some sort of surgery—like cataract removals—that gives them sight for the first time,” added Feller.
The researchers speculated that adenosine’s role in controlling spontaneous neural activity may also explain why mothers taking medication for epilepsy are twice as likely to have children with a set of birth defects known as “fetal anti-convulsant syndrome.” The spontaneous waves of activity occur in the developing visual system of the fetus during the second trimester of pregnancy. Therefore, medications taken by the mother that influence adenosine levels in the brain of the fetus could disrupt the spontaneous activity patterns.
“Understanding adenosine’s role in modulating activity in the developing retina may explain some of the developmental defects seen in fetal-anticonvulsant syndrome,” said Wang, a postdoctoral fellow. “Drugs taken during pregnancy to control epilepsy may have effects similar to adenosine in the developing fetus. The visual problems and other developmental defects characteristic of fetal anti-convulsant syndrome could result from these drugs interfering with the spontaneous activity necessary for patterning the developing nervous system.”
A previous study by Feller and her colleagues showed that the pattern of neural activity is essential for the retinal ganglion cells—which extend projections from the retina to the brain—to form the correct connections in the brain. In mutant mice where the retinal ganglion cells fired randomly, rather than in well-coordinated waves that propagate across the retina from one cell to neighboring cells, these projections were never refined and remained as they were early in development.
To find the factor that might be responsible for coordinating the behavior of the retinal ganglion cells, Feller and Wang took electrical recordings from retinal ganglion cells kept alive in a dish. Following up on work started when Feller was a postdoctoral fellow working with Carla Shatz, a professor of neurobiology at Harvard Medical School, Feller and Wang found that drugs to enhance adenosine’s action increased the frequency of the waves of electrical activity in the cells, and decreasing adenosine’s action decreased their frequency. The electrical recordings showed that adenosine was acting directly on the retinal ganglion cells to alter how easily they could be excited.
These results provide new insight into the mechanism by which the spontaneous electrical activity essential for patterning the developing nervous system is generated, but Feller cautions that they are still preliminary.
“Research into the role of spontaneous neural activity in development has progressed a great deal since the days when it was generally accepted that the genes specified everything except the final fine tuning of connections,” says Feller. “This study sheds light on the important question of how spontaneous activity is generated, but we still have much to learn about the details of the cellular processes involved.”
The study was supported by the McKnight Foundation and the National Eye Institute of the National Institutes of Health.
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