Remembering gets more attention than forgetting, even though forgetting is a part of memory. Similarly, the activation of genes gets more attention than deactivation. Yet deactivation of genes in neurons is essential to learning and memory. When certain genes are activated by physical activity, they promote the formation of neural connections called dendrites. If these genes are not deactivated, dendrites keep proliferating—important connections and unimportant ones alike. The ability to learn new motor skills is impaired.
This phenomenon is the subject of a new study conducted by scientists at Washington University School of Medicine in St. Louis. These scientists, led by Azad Bonni, M.D., Ph.D., head of the Department of Neuroscience at Washington University, scrutinized genes in the cerebellum of mice—the part of the brain responsible for motor functions such as walking—that turn on when the mice are physically active.
“We've shown in mice that genes don't just shut off by themselves; there's an active mechanism to turn off genes after they're turned on,” said Dr. Bonni. “If that mechanism is disrupted in the brain, you see serious consequences for learning and memory.”
Dr. Bonni and colleagues presented their findings July 15 in the journal Science, in an article entitled, “Chromatin Remodeling Inactivates Activity Genes and Regulates Neural Coding.” The article describes how the scientists focused on a large enzyme that binds to genes that turn on when the mice move about, but not to the genes that are not been switched on by movement. The enzyme, known as the nucleosome remodeling and deacetylase (NuRD) complex, appears to be critical to turning off genes. Mice that lack the enzyme are unable to turn off the genes after physical activity ceased.
“Genome-wide analyses in the mouse cerebellum revealed that the nucleosome remodeling and deacetylase (NuRD) complex deposits the histone variant H2A.z at promoters of activity-dependent genes, thereby triggering their inactivation,” wrote the article’s authors. “Purification of translating messenger RNAs from synchronously developing granule neurons (Sync-TRAP) showed that conditional knockout of the core NuRD subunit Chd4 impairs inactivation of activity-dependent genes when neurons undergo dendrite pruning.”
The enzyme, the scientists found, turns off genes by switching out one kind of a DNA-associated protein for another. These proteins, called histones, serve as spools around which the DNA thread is wound, in some places tightly and other places loosely. By switching out one kind of histone for another, the enzyme causes the DNA to be more tightly wound, shutting off any genes in that section of DNA.
“Turning on and off genes is a fundamental property of cell biology, and this is the first epigenetic mechanism that explains how you turn off genes after they're turned on,” asserted Dr. Bonni. “I think we'll find that this mechanism turns off genes in many different contexts.”
During development, neurons form many connections with each other and then prune back all but the most important ones. Neurons in the cerebellum of mice lacking the enzyme do not prune, leaving abnormal connections in place.
Such connections did not affect the mice's ability to walk but did affect their ability to learn motor skills as adults. In people, learning a motor skill would include learning how to play the piano or ride a bicycle.
Adult mice lacking the enzyme were unable to learn how to walk on a rotating rod that gradually sped up, a task other mice could do easily.
“They're walking normally, they're coordinated, but they are really profoundly impaired in learning,” noted Dr. Bonni. “What's really surprising is that these deficits are due not to failure to activate genes but to failure to turn them off.”
Dr. Bonni and colleagues are working on figuring out the mechanism by which changes in gene activity lead to changes in brain cell activity.
“This enzyme is related to other enzymes that are mutated in neurodevelopmental diseases,” Bonni pointed out. “The ability to turn off genes turns out to have profound consequences for brain wiring and learning, and we want to figure out how.”