An Autism Gene Regulates Pain Too

The gene, called SHANK3, affects a well-known protein that transmits pain signals. Image credit: ssilver/123RF Stock Photo.

The gene, called SHANK3, affects a well-known protein that transmits pain signals. Image credit: ssilver/123RF Stock Photo.

Sensory perception is altered in people with autism spectrum disorders (ASDs). Smell, taste, touch, and even pain are exaggerated in some individuals and diminished in others, but it is unknown why and how this happens.

Now, a study in mice and in human pain neurons shows how mutations in SHANK3, a gene strongly associated with autism, could affect the perception of pain. And, the discovery points the way to a possible new approach for pain treatment.

The study was published online December 1 in the journal Neuron.

“It’s a very nice paper in that it merges these two worlds of ASDs and pain, providing an additional perspective on how pain abnormalities and ASDs may be related to one another,” says Michael Caterina, Johns Hopkins University, Baltimore, US, who was not involved in the study.

Clues from a rare condition
People with ASDs are well known to show changes in pain perception. In fact, 77% of individuals with a rare genetic disorder called Phelan-McDermid syndrome (PMS), which features ASD symptoms, have diminished pain sensitivity. Mutations in SHANK3 are seen in 2% of all ASDs, and the gene is completely absent in people with PMS.

“There was some indication that this gene would play an important role in pain. Autism includes many other genes, but PMS primarily involves the deletion of SHANK3 and these patients have changes in pain sensitivity,” says Ru Rong Ji, Duke University School of Medicine, Durham, US, senior author on the paper.

This led Ji to the lab of Yong-Hui Jiang, also at Duke, who had recently created genetically engineered mice lacking SHANK3; these animals exhibit a number of ASD behaviors. Ji was curious to see if the mice also had changes in pain perception, just like humans without the gene do.

First, the researchers asked if the animals missing SHANK3 were unusually sensitive to acute pain, so they tested how they responded to heat, cold, and pressure. They saw no differences, however, between the animals and normal mice.

They then produced chronic pain in the mice by cutting a nerve or injecting an inflammatory substance; these are two common models used to study chronic pain in animals. When the investigators once again tested the animals’ responses to heat, cold, and pressure, this time they found that the mice with chronic pain who were missing SHANK3 responded normally to cold and pressure, but were less sensitive to heat. These results suggested that without SHANK3, painful heat sensation is decreased during chronic pain conditions.

How does SHANK3 affect pain sensation?
The perception of heat is controlled by a protein, called TRPV1, that sits on the surface of pain-sensing neurons. TRPV1 forms a pore that opens at high temperatures to activate nerve cells, sending a pain signal into the spinal cord, which is then relayed to the brain, resulting in the perception of painful heat. Interestingly, TRPV1 also opens in response to capsaicin, the component of chili peppers that makes them hot.

The group wondered if SHANK3 somehow affected TRPV1. They hypothesized that when SHANK3 is missing, as is the case in the mutated mice, TRPV1 would not function as it normally does. If so, this would explain why mice without SHANK3 were less sensitive to heat.

The investigators found not only that SHANK3 protein, made by the SHANK3 gene, was present in pain-sensing neurons that respond to heat, but that it also directly interacted with TRPV1. Without SHANK3, TRPV1 didn’t make its way up to the cell surface, but instead stayed deeper inside the cell where it is made. This drastically reduced the ability of the neurons to detect heat.

From mice to human neurons
The experiments showed that SHANK3 was important for TRPV1 to function properly. in mice. But a critical step in the search for new medicines, including pain drugs, is to test whether findings from animal studies hold up in humans as well.

So the researchers obtained pain-sensing neurons from human donors, and then used a special molecular technique to decrease the amount of SHANK3 in the cells. Just as in mouse pain-sensing neurons, the function of TRPV1 was impaired in these human neurons.

The new study is the first to show how a gene associated with ASDs could change sensitivity to certain forms of pain, helping to explain why people with these disorders have altered pain perception. Importantly, looking beyond ASDs to chronic pain more generally, Ji thinks it may be possible to hinder the interaction between SHANK3 and TRPV1 during chronic pain, perhaps leading to new pain-relieving drugs for patients. —Nathan Fried

To read about the research in more detail, see the related Pain Research Forum news story here.

Nathan T. Fried is a postdoctoral fellow at the University of Pennsylvania, Philadelphia, US.