Autism may be intense world syndrom:
They agreed that the one most like human autism involved rats prenatally exposed to an epilepsy drug called valproic acid (VPA; brand name, Depakote). Like other “autistic” rats, VPA rats show aberrant social behavior and increased repetitive behaviors like excessive self-grooming.
But more significant is that when pregnant women take high doses of VPA, which is sometimes necessary for seizure control, studies have found that the risk of autism in their children increases sevenfold. One 2005 study found that close to 9 percent of these children have autism.
Because VPA has a link to human autism, it seemed plausible that its cellular effects in animals would be similar. A neuroscientist who has studied VPA rats once told me, “I see it not as a model, but as a recapitulation of the disease in other species.”
Barkat got to work. Earlier research showed that the timing and dose of exposure was critical: Different timing could produce opposite symptoms, and large doses sometimes caused physical deformities. The “best” time to cause autistic symptoms in rats is embryonic day 12, so that’s when Barkat dosed them.
At first, the work was exasperating. [...] Markram was ready to give up, but Barkat demurred, saying she would like to shift her focus from inhibitory to excitatory VPA cell networks. It was there that she struck gold.
“There was a difference in the excitability of the whole network,” she says, reliving her enthusiasm. The networked VPA cells responded nearly twice as strongly as normal—and they were hyper-connected. If a normal cell had connections to ten other cells, a VPA cell connected with twenty. Nor were they under-responsive. Instead, they were hyperactive, which isn’t necessarily a defect: A more responsive, better-connected network learns faster.
But what did this mean for autistic people? While Rinaldi was investigating the cortex, Kamila Markram had been observing the rats’ behavior, noting high levels of anxiety as compared to normal rats. “It was pretty much a gold mine then,” Markram says. The difference was striking. “You could basically see it with the eye. The VPAs were different and they behaved differently,” Markram says. They were quicker to get frightened, and faster at learning what to fear, but slower to discover that a once-threatening situation was now safe.
While ordinary rats get scared of an electrified grid where they are shocked when a particular tone sounds, VPA rats come to fear not just that tone, but the whole grid and everything connected with it—like colors, smells, and other clearly distinguishable beeps.
“The fear conditioning was really hugely amplified,” Markram says. “We then looked at the cell response in the amygdala and again they were hyper-reactive, so it made a beautiful story.”