Stuttering in Mice:
Q&A on the Latest Research

Dr. Terra D. Barnes, Dr. Timothy E. Holy, and Dr. Dennis Drayna

Dennis Drayna, Ph.D., has served on the Stuttering Foundation Board of Directors since 2006. He is senior investigator at the National Institute on Deafness and Other Communication Disorders, National Institutes of Health. His current research focuses on using genetic methods to identify the underlying causes of stuttering. Dr. Drayna serves the Foundation as part of his personal commitment to helping those who stutter, and not in his official duty as a scientist at the National Institutes of Health.

How would you sum up your key finding in simple terms?
We have inserted a mutation in a specific gene found in human stuttering into mice.  The mice that carry this mutation exhibit a deficit in the timing of their vocalizations.  This deficit is similar to the vocalization deficit in the speech of humans who carry this mutation.

What led you to consider the effects of this mutation in mice?
First, mutations in other genes (for example the FOXP2 gene) that cause speech disorders in humans have been shown to cause alterations in mouse vocalization.

Second, we wanted a mouse model so that new research avenues into the human disorder would be available.  One application of such a model is in the study of the cellular deficits (the so-called neuropathology) associated with stuttering, which are currently unknown.  A mouse model of stuttering could also be beneficial in research into the development of potential new therapeutic agents for stuttering. 

What do we know about this lysosomal enzyme pathway?
The pathway that targets enzymes to the lysosome is an important and well-studied area in cell biology.  This pathway is responsible for tagging enzymes bound for lysosomes with a mannose-6-phosphate. With the mannose-6-phosphate tag, lysosomal enzymes are trafficked into the lysosomes.   Severe deficits in this pathway give rise to severe neurological and other symptoms in a disorder known as Mucolipidosis II/III.  In contrast, the only known effect of another set of mutations on the same pathway is stuttering. People who stutter and carry these “stuttering” mutations are otherwise neurologically normal (Kang et al. NEJM 362:677-685, 2010). 

How do you describe the changes to the mouse vocalizations? Were they obviously comparable to what happens in people who stutter?
Many aspects of the vocalizations of our mice with the mutation are normal.  What is not normal is the timing, or temporal sequencing, of their vocalizations.  Their vocalizations have longer pauses than those of their littermates without the mutation, and there is evidence for more stereotyped repetitions in their vocalizations. These are very similar in some ways to the stuttered speech of humans who carry the same mutation. 

What are the implications of your findings?
The first implication is that, while mice are not a suitable model for human speech in general, they seem to be quite a good model for analyzing the timing of vocalizations.  Our results indicate there are fundamental mechanisms for vocalization that are common between humans and mice.  This suggests that at least some aspects of human vocalization have evolutionarily conserved roots. 

A second important implication is the method used to analyze the vocalizations of both human and mouse vocalizations.  This new method is fully automated, and makes decisions about abnormalities in vocalization that are independent of subjective judgments or criteria developed for human speech. This method may generalize to other species, thus providing a new tool to study vocalization across the animal kingdom.

Did anything you found come as a particular surprise?
We were very surprised that mice had abnormalities in their vocalization patterns that were similar to that of human stuttering across several measurements.

What would you like for a general audience to take away from this study?
While speech and language are unique to humans, they are based on structures and functions that are encoded in genes that are not unique to humans.  Some aspects of human speech likely have deeply rooted connections to animal vocal communication, even to the extent that we can re-create features of stuttering, a common human speech disorder, in mice. 

What's the next step for you?
One thing we’re particularly interested in is the site within the brain at which these mutations exert their effect.  We know it’s likely to be a very specific and limited area, because our mutation-carrying mice are normal in the other behaviors we can test.  Mice allow sophisticated genetic modifications in which mutations can be expressed in just one part of the brain, or just one type of neuron throughout the brain.  We are hopeful that studies of the vocalizations of such mice can focus our attention on highly specific places within the brain that will then be the focus of further studies.

Anything else you'd like to add?
Stuttering imposes an enormous burden on those that are severely afflicted with the disorder, yet its underlying causes have been very poorly understood.  While it’s surprising that the disorder can, to some degree, be recreated in a mouse, having an experimentally manipulatable animal model for some aspects of this disorder presents many exciting, new opportunities to move research in this area forward.

For more information, contact: 

Terra Barnes, PhD
Washington University School of Medicine
Office: 314-362-3046 

Tim Holy, PhD
Washington University School of Medicine
Office: 314-362-3046

Dennis Drayna, PhD
NIDCD/National Institutes of Health
Office: 301-402-4930

Tamara Bhandari, PhD
Senior Medical Science Writer
Office of Medical Public Affairs
Washington University in St. Louis
Office: 314-286-0122

Melissa McGowan
Office of Health Communication and Public Liaison
NIDCD/National Institutes of Health
Office: 301-496-7243

Jane Fraser
President of the Stuttering Foundation
Office: 912-638-3416