Scientists create mice with features of Tourette’s disorder, advancing research into personalized treatments

In research that could be a step forward toward finding personalized treatments for Tourette’s disease, scientists at Rutgers University-New Brunswick have bred mice that exhibit some of the same behavior and brain abnormalities seen in people with the condition.

As reported in the Proceedings of the National Academy of SciencesUsing a technique known as CRISPR/Cas9 DNA editing, the researchers inserted the same genetic mutations found in people with Tourette’s disease into the corresponding genes in mouse embryos. After the mice were born, the scientists observed their behavior compared to littermates without the gene mutation insertion. The mutations introduced were discovered by some members of the same research team who have focused for more than a decade on investigating genetic factors in Tourette’s disease.

The researchers said the findings indicate that these mice are a very useful model to study the neurobiology of Tourette’s disease and test new drugs.

“There are no drugs specifically designed for Tourette’s disease, and repurposing other drugs has worked poorly, with too many side effects,” said co-senior author Jay Tischfield, the Duncan and Nancy MacMillan Distinguished Professor of Genetics in the Genetics Department at Rutgers. School of Arts and Sciences and a pioneer in the study of Tourette’s disorder. “Until now, the problem has been the lack of an animal model with which to test new or existing drugs.”

Tourette’s disorder is a nervous system disorder that affects children, adolescents, and adults. The condition is characterized by sudden, involuntary movements or sounds called tics. Tics can be mild, moderate or severe and in some cases are disabling.

Tourette’s disorder does not affect lifespan, but it often negatively impacts the experience of people with the disorder and the people they interact with. The Centers for Disease Control and Prevention estimates that one in 162 children has the condition, although the number may be higher.

Using cameras that recorded the mice’s actions and employing a form of artificial intelligence known as machine learning, the researchers found that the genetically engineered mice showed two key characteristics common to people with Gilles de la Disorder. Tourette’s: They engaged in repetitive motor behavior or tics, and they exhibited what they did. neuroscientists call “sensorimotor gating deficits,” a neural process in which the brain filters out unnecessary or irrelevant stimuli.

Cara Nasello, research associate in the Departments of Genetics and Cell Biology and Neuroscience and the study’s first author, said gating deficits in people with Tourette syndrome can be seen as a problem in processing sensory information. A person without the disorder listening to a series of sounds, such as a beeping horn, would not be startled by the first horn, because that person’s brain can link the second and subsequent sounds to the first. Someone with Tourette’s disorder may be startled by every single sound, especially if the volume increases.

The genetically engineered mice responded in the same way that people with the disorder would respond to individual sounds that were part of a pattern: They showed a startle response to each tone, Nasello said.

Working with Miriam Bocarsly of the Department of Pharmacology, Physiology and Neuroscience at Rutgers New Jersey Medical School, the team found evidence that the gene mutations changed levels of a brain chemical known as dopamine. Similar to people with Tourette’s disease who are treated with a drug that changes the amount of dopamine, the processing deficits and repetitive behaviors in the mice decreased in intensity when they were given the same drug.

“An easy way to think about this is that we introduced a gene mutation and it changed the neural circuitry of the mice’s brains,” said Max Tischfield, assistant professor in the Department of Cell Biology and Neuroscience at the Rutgers School of Arts and Sciences and the senior corresponding author of the study. “And those changes change the way a brain chemical like dopamine, which in humans is important for cognition and motor behavior, allows mice’s brain cells to communicate.”

The researchers attributed much of the success of their work to the contributions of families with Tourette’s disease, who donated genetic samples to the research group over the past fifteen years.

“These families did this out of the goodness of their hearts, with the idea of ​​advancing the field,” said Gary Heiman, co-senior author of the study and professor in the Department of Genetics, who recruited families of members with the disease Gilles de la Tourette. around the world and organized blood drives and genetic repositories. “They want to gain a better understanding of this mysterious condition and for us to come up with better treatments, not only for those suffering from the condition now, but also for future generations.”

The scientists said the techniques they used in their study are applicable to researchers studying other complex disorders caused by multiple genes, including autism and schizophrenia.

They also hope that these advances will attract more researchers to study Tourette’s disorder.

“So why would a researcher go into something when little is known and he wonders: how do I even start? What do I have at my disposal that can even scratch the surface of this very complex condition?” said Max Tischfield. “And with these mice we can not only scratch the surface, but also dig underneath.”

Other Rutgers scientists involved in the study include Lauren Poppi, Joshua Thackray, Riley Wang, Rodna Spaseka, CK Johnson and Derek Gordon, from the Department of Genetics; Junbing Wu, Tess Kowalski and Angelina Persaud, from the Department of Cell Biology and Neuroscience; and Miriam Mahboob, from the Department of Pharmacology, Physiology and Neuroscience at Rutgers New Jersey Medical School.

Researchers from Harvard Medical School and Hamad Bin Khalifa University in Qatar also contributed to the study.

-Note: This press release was originally published on the Rutgers University website. Because it has been republished, it may differ from our style guide.