Knockout mice guide future autism therapies

Shank3B mice that mimic typical autism behaviors provide a valuable research tool, according to preclinical trials

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SACRAMENTO, Calif.—Targeted toward developing new personal drugs for people diagnosed with autism, researchers at the UC Davis MIND Institute and Boston Children’s Hospital have completed preclinical trials confirming that Shank3B knockout mice, mimicking typical autism behaviors, provide a valuable research tool toward future therapies. The preclinical study, supported by Autism Speaks, was published online in the journal Molecular Autism on July 15.
“The standard of care for autism is intensive, with early behavioral interventions,” Jacqueline Crawley, co-senior author and the Robert E. Chason Endowed Chair in Translational Research at the MIND Institute, stated in a news release. “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.”
In the Molecular Autism paper, entitled “Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism,” lead author Sameer C. Dhamne and co-author Crawley state in the abstract that to enable the earliest stages of therapeutic discovery and development for autism spectrum disorder (ASD), “robust and reproducible behavioral phenotypes and biological markers are essential to establish in preclinical animal models.”
Behaviors relevant to the diagnostic and associated symptoms of ASD were tested on a battery of
established behavioral tests, the authors state. Assays were designed to reproduce and expand on the original behavioral characterization of Shank3B knockout mice. Two or more corroborative tests were conducted within each behavioral domain, including social, repetitive, cognitive, anxiety-related, sensory and motor categories of assays.
A significant number of patients with ASD harbor SHANK3B mutations. Behaviorally, Shank3B knockout mice exhibited repetitive grooming, deficits in aspects of reciprocal social interactions and vocalizations and reduced open field activity, as well as variable deficits in sensory responses, anxiety-related behaviors, learning and memory. Developed at Duke University, Shank3B knockout mice also replicate abnormal brain electroencephalography (EEG) activity.
To better understand this model, the labs at UC Davis and Boston Children’s Hospital compared two independently bred groups of Shank3B knockout mice and control groups. Researchers replicated and extended previously reported behaviors in Shank3B mice, such as repetitive self-grooming and reduced social interaction.
Led by co-senior researcher Mustafa Sahin, director of 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,” says 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 says. 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 notes.
“The goal of the research is to eventually come up with a therapy or drug that could help people with autism stop their anti-social behaviors,” Crawley tells DDNews. “If successful, this would be the first time people with autism had their own ‘autism drug’ rather than taking ADHD (attention deficit hyperactivity disorder) drugs.”
As she notes of the two FDA- approved ADHD drugs for autism, Risperdol and Abilify: “These are indicated for the treatment of ‘irritability’ in people with autism. Irritability usually means temper tantrums, aggression and self-injury. While these behaviors are difficult to manage, they are not part of the core diagnostic symptoms of autism.”
Combining an effective behavioral intervention with an effective drug treatment may confer synergistic benefits to people with autism, she says. The intervention offered at the MIND Institute is the Early Start Denver Model, which uses group games, crafts, music and dance therapy, yoga and outdoor activities to help participants learn how to make new friends, give and accept compliments, use self-control, manage stress, be good sports and work as part of a team.
Both Crawley and Sahin are principal investigators in the Preclinical Autism Consortium for Therapeutics (PACT) which 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,” says 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.”

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