Genetic Factors, Cellular Trafficking Deficits, and the Role of Neuroglia in Stuttering

Abstract

Genetic approaches have led to major advances in our understanding of persistent developmental stuttering at the molecular and cellular level. While the number of genes found to cause this disorder is still relatively small, most of the genes identified to date encode components of the intracellular trafficking system, a mechanism not previously suggested in stuttering research. Engineering common human stuttering mutations into mice produces animals that are like wild-type mice in most physical and behavioral aspects; however, they demonstrate unusually long gaps and interruptions in their stereotyped vocalizations compared to their non-transgenic littermates. Immunohistochemistry performed on the brains of these mice using a range of antibodies revealed a significant difference in staining with an antibody specific for astrocytes compared to that in non-transgenic littermates. Astrocytes, a glial cell type prominent in white matter tracts, were found to be significantly reduced in the corpus callosum of the transgenic mice. Further studies with cre -driver lines of mice, in which the Gnptab gene was selectively knocked out in a range of specific brain cell types, recreated the vocalization difference only when Gnptab was deficient in astrocytes. Additional studies of mice carrying human stuttering mutations using ultra-high-field-strength diffusion tensor imaging confirmed differences in astrocytes in the corpus callosum and the genu, large white matter tracts that connect the right and left hemispheres of the brain. This focuses attention on interhemispheric communication in stuttering. Together, the availability of reproducible mouse models and an understanding of potential pharmaceutical targets within a specific cell type provide promise for rational pharmaceutical interventions in stuttering.