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Gene Knockout Mouse May Offer Leap Forward in Autism Animal Models

New mouse model exhibits all core autism traits; may offer advantages for testing helpful medicines

This September, scientists at University of California, Los Angeles debuted a new mouse that may represent a more useful animal model for studying autism spectrum disorder (ASD) and testing potential treatments. The mouse shows more behavioral and biological similarities to people with ASD than do most previous mouse models. It also responds to a drug (risperidone) already approved for treating some symptoms of ASD. This suggests that the mice may be particularly suited for testing promising new medicines aimed at relieving autism’s most disabling symptoms.

The strain, first created in 2003, lacks a gene dubbed CNTNAP2, or “cat nap two.” The gene plays a role in brain development. In people, rare inherited mutations in CNTNAP2 can cause a genetic syndrome known as cortical dysplasia-focal epilepsy, whose symptoms can include seizures, loss of language and hyperactivity. Nearly two-thirds of those affected by this rare disorder are also diagnosed with ASD. Daniel Geschwind, M.D., Ph.D., and colleagues at UCLA crossed this mouse strain with another known for its easily observed repertoire of behaviors. He then tested the new hybrids for autism-like traits.

For years, scientists have been genetically engineering mouse models of autism by deleting, or “knocking out,” the mouse versions of genes associated with autism in humans. While most previous mouse models showed only one or two core symptoms of autism, the new cat-nap model shows all three: hampered communication difficulties, social challenges and repetitive behaviors. The mice groom themselves excessively, have difficulty adapting to new situations and also vocalize and play less than do typical mice. In addition, brain studies reveal that the mice exhibit atypical patterns of brain activity and connectivity that are similar to those seen in many people with ASD.

As mentioned, the researchers gave their knockout mice risperidone. The drug is FDA approved to treat ASD-associated “irritability,” which can be accompanied by self-injury, tantrums and aggression. In the mice, the drug significantly reduced repetitive behaviors.

Penagarikano O, Abrahams BS,Herman EI, et al. Absence of CNTNAP2 Leads to Epilepsy, Neuronal Migration Abnormalities, and Core Autism-Related Deficits Cell. 2011 Sept 30 ;147:235–46.


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