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‘Autistic’ mice created – and treated

By Chelsea Whyte

A new strain of mice engineered to lack a gene with links to autism displays many of the hallmarks of the condition. It also responds to a drug in the same way as people with autism, which might open the way to new therapies for such people.

It’s not the first mouse strain to have symptoms of autism, and previous ones have already been useful models for studying the condition. Daniel Geschwind at the University of California, Los Angeles, and colleagues tried a fresh approach, however. Rather than simply examining existing strains to identify mice with autistic-like behaviour, they engineered mice to lack a gene called Cntnap2, which had already been implicated in autism. Cntnap2 is the largest gene on the genome, clocking in at 2.5 million bases, and is responsible for regulating brain circuits involved in language and speech.

Geschwind was initially sceptical that the modified mice would display the behaviour typical of autism in humans, because the neural pathways in the two species are thought to be fairly different. “One has to be cautious,” he says. “What is an autistic mouse going to look like?”

Surprisingly, he says, it turns out to be a lot like a human with autism. “Knockout” mice lacking the gene were less vocal than their genetically unaltered littermates, and less social as well. They also showed repetitive behaviour such as grooming which was “wild almost to the point of self-injury”, says Geschwind. These three symptoms are the ones normally used to diagnose autism in humans.

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Drugged calmer

Next, Geschwind and his team tested a drug approved by the US Food and Drug Administration to treat repetitive behaviour and aggression in people with autism. Risperidone, originally used to treat psychosis, worked on the mice in much the same way it does in humans.

The treated mice were less hyperactive, but still avoided interaction with others. “[The drug] didn’t touch the social behaviours,” says Geschwind. “It just normalised the repetitive behaviours.”

Finally, when the researchers killed the mice and studied their brains, they found that their neurons communicate in an unusual circular way within the frontal lobe, ignoring the rest of the grey matter. This mimics the brains of people with autism.

“It’s clear, based on the study, that the mouse circuitry must be significantly more parallel to humans than we thought before,” says Geschwind.

Human first

“It’s a very exciting result,” says Bhismadev Chakrabarti, a neuroscientist at the Autism Research Centre at the University of Cambridge, who is also at the University of Reading, UK. He is impressed by the “human-first” approach. “They studied autistic patients, then they did brain studies, and then they looked at the mouse models to see if they could effect change [using known therapies].”

Chakrabarti adds that the study strengthens the link between Cntnap2 and autism. “After this paper, Cntnap2 becomes one of the top candidate genes” involved in the condition, he says.

“This opens up the avenue for a systematic battery of tests for this and other genes linked with autism,” says Chakrabarti. “The interaction between genes is really the key next step that we should be looking at.”

Studying the genetics of autism in this way lets researchers separate the symptoms of a disease and find drugs to treat each one. Geschwind says he and his team will next try to dissect the social circuitry of the brain, targeting their work on the development of drug treatments to improve interaction skills.