07:17am Monday 23 October 2017

Researchers Validate Mouse Model for Autism

(SACRAMENTO, Calif.) —

Researchers at the UC Davis MIND Institute and Boston Children’s Hospital have confirmed that mice without the Shank3B protein model aspects of brain physiology and behavioral symptoms observed in people with autism. The findings confirm that Shank3B knockout mice provide a valuable research tool for future efforts to develop new therapies. The study, supported by Autism Speaks, was published in the journal Molecular Autism.

Jackie Crawley

Jackie Crawley

“The standard of care for autism is intensive, early behavioral interventions,” said Jacqueline Crawley, the Robert E. Chason Endowed Chair in Translational Research at the MIND Institute and co-senior author. “In contrast, there are currently no medical treatments that significantly improve the diagnostic symptoms of autism. We are seeking pharmacological targets that correct the biological abnormalities caused by mutations in risk genes for autism.”

Crawley said combining an effective behavioral intervention, such as those offered at the MIND Institute, with an effective drug treatment may confer synergistic benefits to people with autism.

Developed at Duke University, Shank3B knockout mice replicate certain autism symptoms, including repetitive behaviors and abnormal brain electroencephalography (EEG) activity.  A significant number of patients with an autism spectrum disorder harbor SHANK3B mutations.

To better understand this model and how it might support the search for new therapeutics, the labs at UC Davis and Boston Children’s Hospital compared two independently bred groups of Shank3B knockout mice and control groups.

UC Davis researchers replicated and extended previously-reported behaviors in Shank3B mice, such as repetitive self-grooming and reduced social interaction.

Led by co-senior author Mustafa Sahin, who directs Boston Children’s Translational Neuroscience Center, laboratory researchers assessed brain activity in awake mice using EEG methods.

“In each lab, two independently bred cohorts of Shank3B mice and their wildtype littermate controls were tested,” said Crawley. “The behavioral and EEG abnormalities were found to replicate well across the two cohorts in both labs.”

Significant, well-replicated EEG abnormalities and autism-relevant behaviors in Shank3B mice provide an excellent model system for translational evaluation of novel therapeutics for the diagnostic symptoms of autism spectrum disorder, Crawley said. She added that drug testing requires robust, replicable outcomes of a genetic mutation because preclinical studies are designed to detect whether a drug reverses the abnormalities.

“If the deficit is minor and/or ephemeral, investigators could incorrectly conclude that the drug had corrected the abnormality, when in fact they had used a cohort of mice that did not show a strong deficit,” she said.

Both Crawley and Sahin are principal investigators in the Preclinical Autism Consortium for Therapeutics (PACT). Supported by Autism Speaks, PACT investigates models that could accelerate new autism therapies.

PACT is now partnering with drug companies to advance their autism treatments. The next step will be to employ Shank3B and other mouse and rat genetic models to evaluate these and other pharmacological targets.

“We recognize that mice and rats cannot recapitulate the uniquely human symptoms of autism,” said Crawley. “However, a positive finding in autism-relevant behaviors and physiology in a mouse model with a mutation in a human risk gene for autism increases confidence in a drug’s potential benefit.”

Other authors include Jill L. Silverman, Nycole A. Copping and Michael C. Pride at UC Davis; Sameer C. Dhamne, Chloe E. Super, Stephen H.T. Lammers, Mustafa Q. Hameed, Meera E. Modi and Alexander Rotenberg at Boston Children’s Hospital; and Daniel G. Smith at Autism Speaks.

This study was funded by Autism Speaks (awards 8534, 8535, 8702, 8703, 9869 and 9896); and the National Institutes of Health (U54HD079125 and U54HD090255).

 
At the UC Davis MIND Institute, world-renowned scientists engage in collaborative, interdisciplinary research to find the causes of and develop treatments and cures for autism, attention-deficit/hyperactivity disorder (ADHD), fragile X syndrome, 22q11.2 deletion syndrome, Down syndrome and other neurodevelopmental disorders. For more information, visit mindinstitute.ucdavis.edu


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