In 2011, one particular animal made headlines in Nature for ticking that last box. The mice lacked part of SHANK3, a gene mutated in roughly 1 percent of people with autism. The study in which the mice debuted announced triumphantly that they “display autistic-like behaviors,” and the evidence seemed straightforward: The mice showed little inclination to seek out another mouse in the three-chambered assay, a landmark test developed by Silverman’s mentor, Jacqueline Crawley.
In this test, researchers place a mouse in a Plexiglas box containing three rooms laid out in a row, and the rodent faces a simple choice: It can spend time in the first room, where another mouse sits imprisoned in a small wire cage, or it can loiter in a back room, which holds an identical but empty cage. Most mice gravitate toward the playmate. But the SHANK3 visitors moved slowly, pausing frequently to groom. (They groom so compulsively, in fact, that they have bald spots where they’ve licked the fur away.) They sometimes sniffed the empty cage and sometimes the other mouse, showing no real preference for the mouse.
Or at least that’s what the 2011 study found. Last year, Silverman and her colleagues published a study looking at two male and two female groups of the same mice in the three-chambered assay, and found something different. This time, the mice showed behavior that was “mostly normal,” the team wrote, with only one group of male mice displaying social deficits in the three-chambered assay. Around the same time, another team also announced that it was unable to replicate the original results. The upshot: Any social deficits in the SHANK3 mice are, at best, significantly milder than previously reported.
The news confirmed what many scientists had started to suspect. “I felt like I was very naïve,” says Silverman, who now runs her own lab at UC Davis. “The models were coming out and we were like, ‘Oh, we have models now, and we’ve developed these assays, and now we’re really going to start to clear up and have answers,’” Silverman says, “And then we realized of course it’s not so simple.”
The excitement over mouse models has since fizzled. Many of the original reports of social deficits in mice have not held up when tested by independent labs—including Silverman’s—or in different strains of mice. Inconsistent findings have plagued studies not just of SHANK3 mice, but also those with mutations in the risk genes CHD8, NLGN3, NLGN4 and CNTNAP2, among others. That has left many scientists wondering whether mice can ever recapitulate something as complex and human as autism.
“I think that defining an autism mouse is folly,” says Valerie Bolivar, the director of the Mouse Behavioral Phenotype Analysis Core at the Wadsworth Center in Albany, New York. “To get all those things in a nice, neat package with a bow—we’re just not going to get that.”