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Brain cells underlying stuttering identified in mice

After identifying human genes involved in stuttering, researchers are studying the equivalent genes in mice to gain deeper insights into their function. KatarzynaBialasiewicz / iStock / Getty Images Plus

Stuttering is characterized by disruptions in the normal flow of speech. These include pauses and repeated or prolonged sounds, syllables, or words. People who stutter know what they want to say, but they have trouble saying it as quickly as they would like. The condition is most commonly seen in young children. Many outgrow the problem, but about one of every four children who experience stuttering early on continue to have lifelong communication problems.

Researchers believe that stuttering stems from problems with brain circuits that control speech, but precisely how and where these problems occur is unknown. Previous research identified several mutations in genes linked to stuttering in people, including GNPTAB, GNPTG, NAGPA, and AP4E1. These genes play a role in intracellular trafficking, the process of transporting substances needed for functioning around the cell.

To identify changes in the brain brought on by mutations in these genes, a team led by Dr. Dennis Drayna at NIH’s National Institute on Deafness and Other Communication Disorders (NIDCD) genetically engineered mice with a mutation in the mouse Gnptab gene. The team also included researchers at NIH’s National Institute of Mental Health (NIMH) and National Heart, Lung, and Blood Institute (NHLBI). Results were published on August 27, 2019, in the Proceedings of the National Academy of Sciences.

Mice with the Gnptab mutations had abnormally long pauses in their stream of vocalizations, somewhat similar to those found in people with the same mutations. The mutations didn’t have detectable effects on any other mouse behavior tested. The mice with the mutations showed a decrease in a certain type of brain cell called an astrocyte. Astrocytes play a critical role in supporting nerve cells. They carry out a wide range of functions, such as supplying nerve cells with oxygen and nutrients and providing structural support. Other brain cell types didn’t appear to be affected by the mutations.

In the corpus callosum of mice engineered with a human stuttering mutation (lower panel), there are fewer astrocytes, shown in green, than in normal mice (upper panel). Tae-Un Han, Ph.D., NIDCD

The loss of astrocytes was most pronounced in the corpus callosum of the mutant mice. The corpus callosum is the part of the brain that bridges the two hemispheres and enables communication between them. Using advanced MRI methods, the researchers detected a slightly reduced volume of the corpus callosum in the mutant mice.

When the team targeted the Gnptab mutation to specific brain cells, they found that only mice with the mutation in their astrocytes had the stuttering-like vocalizations. Mice with the mutation in other types of brain cells did not show any vocalization problems.

“By taking a genetic approach, we have been able to begin deciphering the neuropathology of stuttering, first at the molecular level by identifying genetic mutations, and now at the cellular level,” Drayna says.

“The identification of genetic, molecular, and cellular changes that underlie stuttering has led us to understand persistent stuttering as a brain disorder,” says Dr. Andrew Griffith, NIDCD scientific director. “Perhaps even more importantly, pinpointing the brain region and cells that are involved opens opportunities for novel interventions for stuttering—and possibly other speech disorders.”