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Developmental biology - Autism

Can Earlier Treatment Help Reverse Autistic Behavior?

Scientists find a sensitive period for reversing social deficits...


New research on autism has found, in a mouse model, that drug treatment at a young age can reverse social impairments. But the same intervention was not effective at an older age.

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. The paper, from Boston Children's Hospital, the University of Texas, Harvard Medical School and Toronto's Hospital for Sick Children, was published in Cell Reports.

Tuberous sclerosis and autism

Many of the hundreds of genes that likely regulate complex cognitive and neuropsychiatric behaviors in people with autism still 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, PhD, at UT Southwestern Medical Center, used a mouse model in which the TSC1 gene was 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. That is one reason why we turned to knocking 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." says Mustafa Sahin MD PhD, Director of the Translational Neuroscience Center and the Translational Research Program at Boston Children's and was the study's senior investigator.

Timing is everything
The new research fed off a previous study published in 2012. In that study, Sahin and colleagues treated the mutant mice starting in the first week of life with rapamycin, a drug approved by the FDA for brain tumors, kidney tumors and refractory epilepsy associated with TSC. They found that they could rescue both social deficits and repetitive behaviors.

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 6 weeks, rescued social behaviors, but not repetitive behaviors or cognitive inflexibility."

More importantly, neither the social deficits nor the repetitive behaviors responded when the treatment was started at 10 weeks.


Mustafa Sahin F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Using advanced imaging, 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.

A new clinical trial?

Based on the mouse findings, Sahin is now seeking funds to test whether early treatment can improve a broad range of autistic-like behaviors in children with TSC. Specifically, he'll explore whether treatment as early as 12 to 24 months can help prevent both social deficits and repetitive inflexible behaviors. He hopes to see better results than in the earlier clinical trial, which involved children ages 6 to 21.

Past research indicates that different autism-related disorders may have different windows of treatment. For example, animal studies of Rett syndrome suggest that treatment can be effective relatively late in life and still improve neurological outcome.

Highlights
• Social behaviors in a cerebellar autism mouse model can be rescued into adulthood
• Sensitive period for repetitive behaviors closes earlier than for social behavior
• Adult rescue of social behaviors in this model requires Purkinje cell survival
• Rescue of cerebellar domain volumes correlates with rescue of specific ASD behaviors

Summary
Despite a prevalence exceeding 1%, mechanisms underlying autism spectrum disorders (ASDs) are poorly understood, and targeted therapies and guiding parameters are urgently needed. We recently demonstrated that cerebellar dysfunction is sufficient to generate autistic-like behaviors in a mouse model of tuberous sclerosis complex (TSC). Here, using the mechanistic target of rapamycin (mTOR)-specific inhibitor rapamycin, we define distinct sensitive periods for treatment of autistic-like behaviors with sensitive periods extending into adulthood for social behaviors. We identify cellular and electrophysiological parameters that may contribute to behavioral rescue, with rescue of Purkinje cell survival and excitability corresponding to social behavioral rescue. In addition, using anatomic and diffusion-based MRI, we identify structural changes in cerebellar domains implicated in ASD that correlate with sensitive periods of specific autism-like behaviors. These findings thus not only define treatment parameters into adulthood, but also support a mechanistic basis for the targeted rescue of autism-related behaviors.

Authors
Peter T. Tsai, Stephanie Rudolph, Chong Guo, Jason P. Lerch, Wade Regehr and Mustafa Sahin.

Peter Tsai, first author on the current paper, is a former postdoctoral fellow in the Sahin Lab at Boston Children's. Other key contributors include Wade Regehr, HMS professor of neurobiology, and Jason Lerch, associate professor at the University of Toronto and research scientist at SickKids.


Acknowledgements
The study was supported by the Nancy Lurie Marks Foundation, the Hearst Foundation, the National Institute of Neurologic Disorders and Stroke, the Tuberous Sclerosis Alliance, the Boston Children's Hospital Translational Research Program and Intellectual and Developmental Disabilities Research Center, the Canadian Institute for Health Research, Ontario Brain Institute and Brain Canada.

About Boston Children's Hospital
Boston Children's Hospital, the primary pediatric teaching affiliate of Harvard Medical School, is home to the world's largest research enterprise based at a pediatric medical center. Its discoveries have benefited both children and adults since 1869. Today, more than 3,000 scientists, including 8 members of the National Academy of Sciences, 17 members of the National Academy of Medicine and 12 Howard Hughes Medical Investigators comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's is now a 415-bed comprehensive center for pediatric and adolescent health care. For more, visit our Vector and Thriving blogs and follow us on social media @BostonChildrens, @BCH_Innovation, Facebook and YouTube.


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Oct 15, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




Research in mice indicates there is a sensitive period for reversing social deficits in tuberous sclerosis complex, a genetic condition commonly including autism spectrum disorder. In the mouse model, the TSC1 gene was only deleted in cerebellar Purkinje cells, also implicated in autism. Credit: Peter Tsai


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