A recent study has found that a gene linked to autism causes mice to have more seizures and anxiety. Dr. Jill Silverman is an assistant professor of psychiatry at the University of California, Davis. She led a team of researchers to study this particular gene in mice. The recently published their results in this year’s July issue of Human Molecular genetics.
What was the gene that they studied?
The gene the researchers studied was called UBE3A. It’s found in a lot of tissues including skin, stomach lining, and the brain. UBE3A can code several different proteins. One protein is actually an enzyme that cleans up other proteins by tagging them for destruction. This is helpful for cells to get rid of proteins they no longer need. Other studies found that UBE3A also makes proteins that are able to regulate the levels of other genes.
The role of UBE3A in the brain
This enzyme has an interesting function in the brain. It seems to control communication between neurons and is related to how they are structured. For example, there are different levels of this enzyme depending on how many neuron connections are present. Because of this, it’s believed that UBE3A is also related to memory and learning.
What is UBE3A’s role in autism?
Right now, we don’t know the exact role of UBE3A in autism. However, there are some studies on animals that show a connection of this gene with Angelman syndrome. This syndrome is a very rare disorder that can sometimes be mistaken for cerebral palsy or autism. Kids with Angelman’s are usually described as unusually happy kids with developmental delay. They have trouble with speaking and commonly suffer from seizures as well as motor disorders. Some scientists believe there is a genetic association between Angelman’s and autism. They think that UBE3A might also be related to autism disorder.
How is UBE3A connected to autism and Angelman’s?
UBE3A is a gene that is found on one of your chromosomes, 15q11.2. This particular chromosome has been linked to causing disorders like autism. Doctors call this syndrome the Dup15q syndrome. This syndrome helps describe the trend we see whenever someone has two or more copies of this chromosome. When someone has this, they tend to also have many neurologic symptoms including anxiety, developmental delay, and seizures. The syndrome can also affect speech and motor functions. A lot of these people have problems with coordination and muscle tone.
How did Dr. Silverman study this in mice?
To study this gene further, Dr. Silverman and her team developed genetically manipulated mice. They specifically engineered their mutant mice to produce a large amount of Ube3a protein. They saw that these mice had particularly high levels in the excitatory neurons of the cortex and hippocampus. The researchers then compared their mutant mice with their normal mice to try and detect behavioral differences.
What did the research team find?
Mice overexpressing Ube3A seemed to be more anxious.
The team noticed mice with more Ube3A seemed to be more anxious. These mice were less likely to go from dark to light areas in their cage. They think this might be a sign of higher anxiety since well-lighted areas are more exposed. The researchers also put extra chambers to test the movement behavior in their mice. They found their mutant mice were less likely to move between the rooms and preferred to stay in one. Lastly, they tested their body temperatures to gauge stress response. It seemed that compared to normal littermates, the mice with more Ube3a would have more striking spikes in body temperature when faced with stress. These findings suggest a relationship between higher Ube3a and a more anxious mouse.
High levels of UBE3A might cause learning and memory problems.
The mutant mice seemed to have some problem making memories and learning fear conditioning. To study this, the mice received a cue before being shocked. They were placed in specific environments with unique smells, lighting, shapes, or floor texture right before the shock. They also repeated this model with sound cues as well, playing specific tones for mice to hear. To measure whether or not they made a connection between the cue and the shock, they recorded how long the mouse would freeze from fear when re-exposed to the cue. Normally, a mouse would recognize the unique cues and become very fearful of the shock to come, showing the researchers that it had learned the two are connected. The mice with more UBE3A were less likely to make these connections, suggesting a problem with learning and memory.
UBE3A levels did not have any effect on social behaviors.
The researchers also studied autism related behaviors in their mice. They would record the amount of time their mice spent sniffing new objects or other mice as a measure of sociability. They also recorded the time they spent exploring when placed in a new environment. Lastly, the looked at how well they groomed themselves. They didn’t find that their mutant mice were any less social or explorative. Both types of mice were also equally good at cleaning themselves.
Mice with more Ube3A were more likely to have seizures.
The team believes that high levels of Ube3a might increase the risk for seizure. Dr. Silverman noticed that mutant mice were more likely to die during the study. She was suspicious that some of them might have had seizures. To examine this, they recorded brain waves to monitor these mice as they moved around and slept, and they also used a chemical to induce seizures in their mice. They found that mice with more Ube3A were faster to get seizures when given the chemical.
Mice with UBE3A might have more subtle motor problems.
Last year, Dr. Silverman’s team had also tested the mice ability to cross narrow beams. They found that the mutant mice slipped more often. Even though they didn’t see any obvious difference in motor ability between normal and modified mice, the beam test might point to a more subtle difference in motor skills. The mice with more UBE3A protein might have trouble with fine-motor functions.
Mutant mice had smaller brains on imaging.
Lastly, the scientists took images of the mice brains. They found that the brain was much smaller overall in their genetically modified mice. The biggest differences in size were in the cortex, hippocampus, amygdala, and striatum.
What can we do with all this information?
Dr. Silverman and her team went one step further to try and solve the problems created by high levels of Ube3A. They hope to turn off this extra gene! Currently, they are using a drug called doxycycline to deliver a special molecule that turns off the extra copy of 15q11.2. They found that after injecting this drug, their modified mice would seem much less anxious when placed back in their cages. The team plans to continue studying the effects of their experimental treatment.
What this means for the future
What Dr. Silverman and her team found in their genetically modified mice help us better understand ways we can help people with autism or Angelman’s. It’s exciting to know that there might be a way to correct the genetic causes for some of these disorders.
There is still so much work to be done! Dr. Silverman has only tried to study this in mice. On top of that, the results her team found are not without competition. Other researchers found that their mice with high Ube3A were less social than Dr. Silverman’s mice. Dr. Silverman says that this may be because of subtle differences in where the protein was expressed as well as the type of mouse that was used. More studies will need to be done to really understand how this extra gene affects the human brain.