Autism spectrum disorders are primarily thought of as disorders of the brain, generally characterized by repetitive behaviors and deficits in communication skills and social interaction. But a majority of people with autism spectrum disorders also have an altered tactile sense; they are often hypersensitive to light touch and can be overwhelmed by certain textures. “They tend to be very wary of social touch [like a hug or handshake], or if they go outside and feel a gust of wind, it can be very unnerving,” says neuroscientist Lauren Orefice from Harvard Medical School in Boston.
An appreciation for this sensory aspect of autism has grown in recent years. The newest version of psychiatry’s bible, the Diagnostic and Statistical Manual of Mental Disorders, includes the sensory abnormalities of autism as core features of the disease. “That was a big nod and a recognition that this is a really important aspect of autism,” says Kevin Pelphrey, a cognitive neuroscientist at The George Washington University in Washington, D.C., who was not involved in the work.
The sensation of touch starts in the peripheral nervous system—in receptors at the surface of the skin—and travels along nerves that connect into the central nervous system. Whereas many autism researchers focus on the end of the pathway—the brain—Orefice and colleagues wondered about the first leg of the trip. So the group introduced mutations that silenced genes associated with autism spectrum disorders in mice, adding them in a way that restricted the effects to peripheral nerve cells, they report today in Cell. The team singled out the gene Mecp2, which encodes a protein that regulates the expression of genes that help forge connections between nerve cells.
The Mecp2 mutant mice were more sensitive to light touch; a small puff of air on their backs startled the rodents more than normal mice. Additionally, the mutants were unable to distinguish between rough and smooth textures. Just like normal mice—which love novelty—they played with new objects whenever given a choice between familiar and new ones that differed in shape and size. But when the objects differed by texture, they played just as much with familiar, rough blocks of wood and new, smooth ones—unlike the control mice. Orefice suggests that an increased sensitivity to touch in the mutant mice makes any texture overwhelming, so subtle differences are indistinguishable.
The animals also displayed autismlike behaviors beyond touch. Even though the defective Mecp2 gene wasn’t present in brain cells, the mutant mice were also more anxious and less social, traits generally attributed to the central nervous system. When given the option to hang out with another mouse or an object like an empty cup, the mutant mice spent just as much time with the object as with the other mouse, unlike normal mice, which prefer a living companion. Tests of anxiety also revealed differences. Whereas normal mice will explore the entirety of an open area or venture onto the wall-less sides of an elevated platform, the mutant mice preferred to hug the edges of the open area and remain in the walled regions of the platform, suggesting heightened anxiety.
When the researchers silenced the genes in the peripheral nerves of adult animals, they were still hypersensitive to light touch, but they didn’t display the behavioral abnormalities seen in the animals that had the gene silenced from birth. That suggests to Orefice’s team that there is a developmental window of time when touch influences behavior. “The way we navigate our world is largely with a sense of touch,” she says. During development, touch is key to learning how to interact with other animals and the environment. If a light touch from another mouse is uncomfortable, a mouse might learn to avoid its peers in the future. And if the environment itself feels abrasive, the mouse might stop exploring.
The researchers also found that the peripheral nerves of Mecp2 mutant mice had low levels of a receptor for the neurotransmitter GABA (gamma-aminobutryic acid). Low GABA levels in the brain have previously been linked to autism, but the new finding opens up an unexpected treatment possibility: a drug that restores GABA function in the periphery. “If we can normalize the hypersensitivity to touch, it’s possible that this might help improve anxietylike behaviors and social interaction deficits. This is not to say that the brain is not important,” Orefice says. But targeting the periphery along with the brain may be a way to get at the disease from both ends.
For now, the findings apply only to mice, which are an imperfect model for complex cognitive disorders such as autism. “For translation to humans, it would be important to know if pharmacological enhancement—ideally of the specific GABA receptor—can alleviate the peripheral hypersensitivity to touch, especially in young children who may be in a critical period of vulnerability,” says Takao Hensch, a neuroscientist at Harvard University who was not involved in the research. He also wonders whether the findings apply to other genetic forms of autism spectrum disorders. Mecp2 has been shown to have unique effects on GABA in the brain; perhaps its peripheral effects are unique as well.
Still, the finding that dysfunction in the touch system can contribute to behavioral problems is exciting, Pelphrey says. “It gives you a sense of how fundamental these sensory features might be … in terms of mechanistically causing some of the other features,” he says. “It really opens up a different way of thinking about what’s going on.”
(Source: sciencemag.org)
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