What the mouse thinks:
Researchers are also thinking about assays that may better capture the nuances of autism — such as tests of social behavior that borrow from studies of reward. For example, an autism mouse might not be inclined to revisit a corner of a cage where it once had a rewarding interaction with a peer, says Ted Abel, director of the Iowa Neuroscience Institute at the University of Iowa. But he cautions against inferring too much about what the mouse might be thinking. Instead of looking for a mouse example of a particular trait, he says, researchers should document all behavior in the animal with no bias. “We should study the mice and see what they tell us — try to discover something we don’t know, as opposed to assuming we do know,” he says.
A few teams are following this best-practice guideline, including the two that reassessed the SHANK3 model last year. One group of researchers, the Preclinical Autism Consortium for Therapeutics (PACT), is focused on finding the best possible mouse model for screening treatments. The SHANK3 model, the group says, is still the best option for this purpose. The other team is carefully assessing features in a range of mice, including those with mutations in CNTNAP2.
Animal studies should mimic clinical trials in people, says Patricia Kabitzke, a researcher on the second project and senior scientific program manager at Cohen Veterans Bioscience, a nonprofit research organization in New York. In clinical trials, researchers are required to state the parameters of their experiments in advance and then publish their findings, whether positive or negative, rather than interpreting the results they get. If mouse studies don’t follow this practice, she says, some teams may repeat their experiments multiple ways, with multiple assays, until they get the result that best fits their paradigm.
None of the autism mice Kabitzke’s team has looked at so far, including two SHANK3 mutants, show reliable social deficits. But that doesn’t mean the mice aren’t useful, she says, because they have other traits that may prove consistent. “At the end of the day, I am not sure how necessary it is going to be to try to recapitulate exactly the same symptoms in the animal as you see in the human,” she says. “It’s kind of an absurd proposition to think that we have a mouse model, or rodent model, or really any kind of model of anything. We really don’t even have a human model of a disease, because there’s so much variation in how these differences present themselves.”
The key to truly understanding behavior may be to slow down and chart it manually. Bolivar trained with a scientist who learned animal behavior from zoologist Robert Hinde, who mentored legendary primatologists Jane Goodall and Dian Fossey. This makes Bolivar a “dinosaur,” she says, but also well equipped to study the behavior of a species that is different from people.
Even then, scientists are inferring intent when they decide, for example, that sniffing a nose is a social act. “I have probably scored more social interactions than anybody on earth,” says Yang, who got her start in science 12 years ago testing the first autism mouse models for social deficits. “I scored this nose-to-butt sniffing for 10 years, but do I really understand [it]?”
Watching animals behave for dozens of hours is the only way for researchers to make sure they don’t misinterpret anything, Bolivar and others say. Scuffling mice might be playing or fighting, and grooming can be a show of either affection or dominance, depending on the degree of pressure involved, for example. In Bolivar’s lab, students sit and watch videos in which pairs of mice sniff, scurry and tumble together in small Plexiglas cages. The students take note each time the mice do one of 11 things, such as touching noses, sniffing rears or grooming themselves. It is slow, painstaking work.
In one video, a mouse watches as the gloved hand of a researcher descends, holding another mouse. The first mouse immediately runs over, and the two mice touch noses several times, then sniff each other’s heads and backsides. By one minute in, the first mouse is following the second rapidly across the cage. By three minutes, they are rolling across the cage in a blur of fur and whiskers. What this really means, only the mice know for now.
But Silverman hopes to find out. She, too, is carefully observing one-on-one interactions as a way to look for social deficits in mice, although she has yet to see an animal that fits the bill. “I haven’t totally given up,” she says.