Deleting a certain gene in mice unlocks a mysterious area of the brain that is otherwise considered relatively inflexible, according to scientists at Emory University School of Medicine.
Mice with a disabled RGS14 gene have an easier time navigating through mazes and a stronger memory than average mice, suggesting that the presence of RGS14 limits some types of learning.
Because RGS14 seems to hold mice back mentally, John Hepler, PhD, professor of pharmacology at Emory University School of Medicine, says he and his colleagues have been jokingly calling it the “Homer Simpson gene.”
The gene RGS14 is primarily activated in one particular part — named CA2 — of the hippocampus, a well-researched area of the brain involved in merging new ideas and forming new memories. The CA2 region, however, lies off the beaten path scientifically and it’s not clear what its functions are, says Hepler.
RGS14, which is also found in humans, was discovered over a decade ago. Hepler and his colleagues have formerly shown in other studies that RGS14 is a key control protein that regulates molecules involved in processing various types of signals that are associated with learning and memory.
To further investigate RGS14’s functions, graduate student Sarah Emerson Lee characterized mice whose RGS14 genes were disabled through gene-targeting technology. Along with Serena Dudek, PhD, of the National Institute of Environmental Health Sciences, she observed how the CA2 region in the gene-altered mice responded to electrical stimulation.
Other studies have shown how other regions of the hippocampus use long-term potentiation, a process of strengthening connections between neurons that can actually be witnessed in a culture dish after new memory formation. The CA2 region, however, is different from other regions in that it is resistant to long-term potentiation.
Another difference in the CA2 region is that the neurons are more capable of surviving injury by seizures or stroke than the neurons in other areas of the hippocampus.
The researchers were surprised to discover that, in mice with a disabled RGS14 gene, the CA2 region was now capable of “robust” long-term potentiation. In other words, when electrically stimulated, the neurons there made even stronger connections.
Later, the gene-altered mice were able to recognize objects previously placed in their cages better than the normal mice. They were also more skilled at navigating through a water maze to a hidden escape platform because they better remembered visual cues.
“A big question this research raises is why would we, or mice, have a gene that makes us less smart – a Homer Simpson gene?” Hepler says.
“I believe that we are not really seeing the full picture. RGS14 may be a key control gene in a part of the brain that, when missing or disabled, knocks brain signals important for learning and memory out of balance.”
Having a disabled RGS14 doesn’t appear to hurt the altered mice, but their brain functions may have been altered in a way that researchers haven’t yet identified. Besides being resistant to injury by seizure, certain kinds of CA2 neurons are lost in schizophrenia, and loss of another gene turned on primarily in the CA2 region alters social behaviors, Hepler notes.
“This suggests that these mice may not forget things as easily as other mice, or perhaps they have altered social behavior or sensitivity to seizures,” he says. “But not necessarily.”
“The pipe dream is that maybe you could find a compound that inhibits RGS14 or shuts it down,” he adds. “Then, perhaps, you could enhance cognition.”
At Emory, collaborators included Kerry Ressler, MD, PhD, associate professor of psychiatry and behavioral sciences, Yoland Smith, PhD, research professor of neurology (both at Yerkes National Primate Research Center), David Weinshenker, PhD, associate professor of human genetics and Yue Feng, PhD, associate professor of pharmacology, with additional contributions from J. David Sweatt, PhD, chair of neurobiology at University of Alabama, Birmingham.
The results are published online in the Proceedings of the National Academy of Sciences, and the research was supported by the National Institutes of Health.
Source: Emory University