Study Reveals How Syngap1 Gene Affects Touch-Based Perception in Mice

You may scarcely notice it, but much of what you do every day requires your brain to engage in perceptual learning. To safely cross an intersection or quickly retrieve something from your bag, you depend upon your brain to first assign meaning to sensory input from your eyes or fingertips.

Usually, it's effortless.

Research from The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology shows a gene called Syngap1 enables touch-based perception, while certain mutations can lead to mixed signals. The research was made possible through grants from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke, both part of the National Institutes of Health.

The study, published in January in Nature Communications, focuses on the sense of touch, exploring in detail how errors in the Syngap1 gene lead to disrupted perceptual learning in mice, said lead author and neuroscience professor Gavin Rumbaugh, Ph.D. This study is also relevant for understanding other conditions, including schizophrenia and Parkinson's disease, in which sensory and movement-related processes no longer work together properly, the researchers said.

In people, mutations to the Syngap1 gene can cause autism and intellectual disability. For neurotypical people, the brain automatically assigns meaning to sensory input, like the sight of a red light or the smooth texture of a pen, Rumbaugh said.

"Kids with these disorders, their brains don't necessarily derive proper meaning from input from the senses, and therefore it's difficult for them to adjust their behavior," he said. "But no one really understands what goes wrong in the brain to diminish their perceptual learning."

This study offers possible answers. In their experiments, the team documented disruptions in the brain's ability to interpret touch-based information and respond properly.

"We found that touch encoding is upside down in Syngap1 models," Rumbaugh said.

People have two copies of most of their genes, one from each parent. Mutations can change or silence one or both copies. In the case of the Syngap1 gene, research has shown that two working copies are required for proper brain development. Mutations can cause autism traits, intellectual disability and disordered sensory processing.

Going in, the researchers understood the gene Syngap1 enabled touch perception. In a study published in Nature Neuroscience in 2018, Rumbaugh's lab documented the experiences of families of children who carry an altered copy of the gene. The children did not respond normally to touch and often had abnormally high pain tolerance. In one case, a child ignored his broken finger for four days.

In follow-up experiments with mice, Rumbaugh's team found corresponding changes in the part of the brain that processes sensory information.

For the latest study, co-first authors Thomas Vaissiere, Ph.D., a staff scientist, and Sheldon Michaelson, Ph.D., a postdoctoral researcher, investigated how mice with typical or mutated versions of the gene explored their environment with their whiskers. In one experiment, conducted in the dark, the mice were tasked with recognizing one of two poles as new, based on vertical grooves.

"An analogy would be reaching into your handbag after someone says, 'I want you to get your lip balm, but not your pen,'" Rumbaugh said.

Unlike the typical mice, those with an altered copy of Syngap1 could not tell the difference between textures. In the typical mice, a more forceful touch - meaning a deeper bend to the whisker - produces more electrical signals among brain cells. However, in rodents with the mutated gene, researchers found the pattern turned upside down. For them, a strong touch and a pronounced bend sparked less neuron signaling than a weak touch.

Consequently, these mice performed their tasks based on inaccurate information, an experience akin to rifling through your bag while wearing gloves. This altered input made it difficult for them to pay attention, the scientists wrote. What's more, they frequently gave the wrong answer.

The mice couldn't adjust their behavior to fit the circumstances, Rumbaugh said. His lab is working to identify compounds to elevate production of the protein that Syngap1 makes, as a possible treatment for the condition.

The studies were conducted in adult mice. Looking ahead, Vaissiere said he wants to look more closely at how the mutation affects brain development as well as its role in other senses.