Brain circuitry behind autism identified

London, July 3 (ANI): Researchers have found that deleting a single gene in the cerebellum of mice can cause key autistic-like symptoms.

They also discovered that rapamycin, a commonly used immunosuppressant drug, prevented these symptoms.

The deleted gene is associated with Tuberous Sclerosis Complex (TSC), a rare genetic condition. Since nearly 50 percent of all people with TSC develop autism, the researchers believe their findings will help us better understand the condition’s development.

“We are trying to find out if there are specific circuits in the brain that lead to autism-spectrum disorders in people with TSC,” said Mustafa Sahin, Harvard Medical School associate professor of neurology at Boston Children's Hospital and senior author on the paper.

“And knowing that deleting the genes associated with TSC in the cerebellum leads to autistic symptoms is a vital step in figuring out that circuitry,” he noted.

This is the first time researchers have identified a molecular component for the cerebellum’s role in autism.

“What is so remarkable is that loss of this gene in a particular cell type in the cerebellum was sufficient to cause the autistic-like behaviours,” said Peter Tsai, HMS instructor of neurology and the first author of this particular study.

TSC is a genetic disease caused by mutations in either one of two genes, TSC1 and TSC2. Patients develop benign tumors in various organs in the body, including the brain, kidneys and heart, and often suffer from seizures, delayed development and behavioural problems.

Researchers have known that there was a link between TSC genes and autism, and have even identified the cerebellum as the key area where autism and related conditions develop.

Previous studies have shown that certain cells essential for cerebellar function called Purkinje cells, which are among the largest neurons in the human brain, are fewer in number in patients with autism. To better understand the relationship between Purkinje cells and autism, Sahin and his team deleted copies of the TSC1 gene in the Purkinje cells of mice. Some mice had only one copy of the gene deleted, while others had both of their copies deleted.

In both cases, deleting this gene caused the three main signs of autistic-like behaviours: abnormal social interactions, repetitive behaviours, and abnormal communication.

The researchers also tested learning. “These mice were able to learn new things normally,” said Tsai, “but they had trouble with ‘reversal learning,’ or re-learning what they had learned when their environment changed.”

“These changes in behavior indicate that the TSC1 gene in Purkinje cells, and by extension, the cerebellum, are a part of the circuitry for autism disorders,” emphasized Sahin.

The researchers also found that the drug rapamycin averted the effects of the deleted gene. Administering the drug to the mice during development prevented the formation of autistic-like behaviours.

Currently, Sahin is the sponsor-principal investigator for an ongoing Phase II clinical trial to test the efficacy of everolimus, a compound in the same family as rapamycin, in improving neurocognition in children with TSC. The trial will be open for enrollment until December 2013.

These findings were published online July 1 in Nature. (ANI)