The findings appear in the June 22 online edition of the journal Nature Medicine.
TSC is a devastating genetic disorder that disrupts brain function, often causing severe mental retardation. Even in mild cases, learning disabilities and short-term memory problems are common.
Using a mouse model for TSC, UCLA scientists tested rapamycin, a drug approved by the federal Food and Drug Administration to fight tissue rejection following organ transplants. Rapamycin is well known for targeting an enzyme involved in the production of proteins needed for memory. The UCLA team chose the drug because the same enzyme is also regulated by TSC proteins.
"This is the first study to demonstrate that the drug rapamycin can repair learning deficits related to a genetic mutation that causes autism in humans," said principal investigator Dr. Alcino Silva, professor of neurobiology and psychiatry at the David Geffen School of Medicine at UCLA. "The same mutation in animals produces learning disorders, which we were able to eliminate in adult mice. Our work and other recent studies suggest that some forms of mental retardation can be reversed, even in the adult brain."
"These findings challenge the theory that abnormal brain development is to blame for mental impairment in tuberous sclerosis," said first author Dan Ehninger, a UCLA postgraduate researcher in neurobiology. "Our research shows that the disease's learning problems are caused by reversible changes in brain function - not by permanent damage to the developing brain."
Silva and Ehninger studied mice bred with TSC and verified that the animals suffered from the same severe learning difficulties as human patients. Next, the UCLA team traced the source of the learning problems to biochemical changes that spark abnormal function of the hippocampus, a brain structure that plays a key role in memory.
"Memory is as much about discarding trivial details as it is about storing useful information," said Silva, a member of the UCLA Department of Psychology and UCLA Brain Research Institute. "Our findings suggest that mice with the mutation cannot distinguish between important and unimportant data. We suspect that their brains are filled with meaningless noise that interferes with learning."
"After only three days of treatment, the TSC mice learned as quickly as the healthy mice," Ehninger said. "The rapamycin corrected the biochemistry, reversed the learning deficits and restored normal hippocampal function, allowing the mice's brains to store memories properly."
In January, Silva presented his study at a meeting of the National Institute of Neurological Disorders and Stroke, where he was approached by Dr. Petrus de Vries, who studies TSC patients and leads rapamycin clinical trials at England's University of Cambridge. After discussing their respective findings, the two researchers began collaborating on a clinical trial currently taking place at Cambridge to examine whether rapamycin can restore short-term memory in TSC patients.
TSC strikes one in 6,000 people, making it twice as common as Huntington's disease or Lou Gehrig's disease.
"The United States spends roughly $90 billion a year on remedial programs to address learning disorders," Silva said. "Our research offers hope to patients affected by tuberous sclerosis and to their families. The new findings suggest that rapamycin could provide therapeutic value in treating similar symptoms in people affected by the disorder."'
The research was funded by the National Institute of Neurological Disorders and Stroke, Autism Speaks and Deutsche Forschungsgemeinschaft (German Research Foundation).
Silva and Ehninger's co-authors included Yu Zhou, Carrie Shilyansky and Weidong Li, of UCLA, and Sangyeul Han, Vijaya Ramesh and David Kwiatkowski, of Harvard University Medical School.