Earlier treatment can help reverse social impairments in tuberous sclerosis patients, but the same treatment is not effective at an older age, reports a new mice study. The findings of the study are published in the journal Cell Reports.
The study is the first to shed light on the crucial timing of therapy to improve social impairments in a condition associated with autism spectrum disorder.
Many of the hundreds of genes that likely regulate complex cognitive and neuropsychiatric behaviors in people with autism remain a mystery. However, genetic disorders such as tuberous sclerosis complex, or TSC, are providing clues. Patients often have mutations in the TSC1 or TSC2 gene, and about half develop autism spectrum disorder.
The investigators, led by Peter Tsai, MD, Ph.D., at UT Southwestern Medical Center, used a mouse model in which the TSC1 gene is deleted in a region of the brain called the cerebellum.
"There were several mouse models of TSC previously published, but they all had seizures and died early in life, making it difficult to study social cognition," says Mustafa Sahin, MD, PhD, who directs the Translational Neuroscience Center and the Translational Research Program at Boston Children's and was the study's senior investigator.
"That is one reason why we turned to knock out the TSC1 gene only in cerebellar Purkinje cells, which have been implicated in autism. These mice have normal lifespans and do not develop seizures."
But when a similar drug, everolimus, was tested in children with TSC, neurocognitive functioning and behavior didn't significantly improve. Sahin and his colleagues wondered whether there was a specific developmental period during which treatment would be effective. The new mouse study delineates not only the timeframe for effective rapamycin treatment of certain autism-relevant behaviors but also some of the cellular, electrophysiological and anatomic mechanisms for these sensitive periods.
"We found that treatment initiated in young adulthood, at six weeks, rescued social behaviors, but not repetitive behaviors or cognitive inflexibility," says Sahin.
More importantly, neither the social deficits nor the repetitive behaviors responded when the treatment was started at ten weeks. Using advanced imaging, the researchers went on to show that the rescue of social behaviors correlates with reversal of specific MRI-based structural changes, cellular pathology, and Purkinje cell excitability. Meanwhile, motor learning rescue appeared independent of Purkinje cell survival or rescue of cellular excitability.
Inflammation may be playing a role in the development of epilepsy in Tuberous Sclerosis Complex (TSC) patients, suggested Dr. Michael Wong and his laboratory.
The first drug study aimed at preventing or delaying the onset of epilepsy in children with tuberous sclerosis complex has been launched by researchers.