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One Gene, One Drug Affect Autism Behaviors in Mouse Model

Harvard researchers found that deleting one gene in certain brain cells causes autism behaviors in mice. They also discovered that treating the mice with rapamycin, an immunosuppressant drug, prevents the symptoms. Autism Speaks partially funded the study, published this month in the journal Nature.

The findings represent an important step in figuring out brain pathways that cause autism, explains the study’s senior author, Mustafa Sahin, Ph.D., associate professor of neurology at Harvard University. It also represents a very early step in determining whether rapamycin or drugs like it can help individuals with autism.

Past research has associated autism with certain brain cells in the cerebellum, a region involved in coordinating brain activity. These cells, called Purkinje cells, play an essential role in normal brain function. Studies using post-mortem tissue show that many individuals with autism have fewer of these cells than is normal.

Dr. Sahin and his team wanted to better understand the link between Purkinje cells and autism. They deleted one gene in the Purkinje cells of mice. Specifically, they deleted a gene associated with the rare disorder tuberous sclerosis complex (TSC). Nearly half of all individuals with TSC develop autism. Studying single-gene disorders associated with autism helps researchers pinpoint affected brain circuits and test potential treatments, Dr. Sahin explains.

Deleting the gene (either one or both copies) caused all three of autism’s core behaviors:

· Abnormal social interactions. The mice spent less time with each other and more with inanimate objects.

· Repetitive behaviors. The mice spent abnormal amounts of time pursuing one activity.

· Abnormal communication. They emitted abnormal levels of ultrasonic vocalizations.

The researchers found that the Purkinje cells became less active in the mice with the deleted gene. “These are the only cells the cerebellum uses to send information out to other regions of the brain,” explains Dr. Sahin. “The whole cerebellum becomes less effective if Purkinje cells are not functioning.”

When the researchers treated the mice with rapamycin, however, the autism-like behaviors did not appear. “This is really important because it suggests all the core features can be blocked with this small molecule,” Dr. Sahin says.

Rapamycin inhibits an enzyme, called mTOR. In TSC, the biological pathway controlled by this enzyme becomes hyperactive. “We believe rapamycin’s effect in preventing autistic-like behaviors is due to mTOR inhibition and not due to immunosuppression,” Dr. Sahin says.

“The promise of translating results from animal studies into treatments for individuals with autism is the crux of why we fund studies like Mustafa’s,” says Daniel Smith, Ph.D., Autism Speaks senior director of discovery neuroscience. “His results are an important advance in our understanding of the complex relationship between Perkinje cell circuits, TSC and behavioral symptoms of autism and therapeutic intervention. Studying his model to learn how these circuits and behavior change over early life development and respond to treatments is critical. Even more important will be using brain imaging to look for similar findings in people with TSC and autism.”

Dr. Sahin and colleagues are already using a rapamycin-like drug in a clinical trial in patients with TSC (also partially funded by Autism Speaks). It will help determine whether the drug can improve autism symptoms specifically in children with TSC. If these trials show promise, future studies will be required to understand if these effects can be achieved safely in patients who have other causes of autism.

Dr. Sahin’s team also plans to continue its work with animals by using rapamycin during different periods of development. In this way, they may identify sensitive periods of brain development that may be optimal for treatment. Their plans also include using brain-imaging techniques to better understand cerebellum activity and overall brain connectivity in infants with TSC and others at risk for developing autism.

Autism Speaks continues to fund research into the brain biology of autism with the goal of finding treatments that can help children and adults affected by the disorder. You can explore these and hundreds of other Autism Speaks studies using this website’s Grant Search.