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Disruption of iron homeostasis in stuttering mice: Accumulation of iron deposits near regional astrocytes of GNPTAB-mutant mice
Poster E3 in Poster Session E, Thursday, October 26, 10:15 am - 12:00 pm CEST, Espace Vieux-Port
Camryn Bragg1, Marissa Millwater1, Max Weinhold1, Afuh Adeck1, Ruli Zhang1, Shahriar SheikhBahaei1; 1National Institute of Neurological Disorders and Stroke (NINDS), Neuron-Glia Signaling and Circuit Unit, Bethesda, MD, USA
Stuttering is a neurodevelopmental disorder characterized by involuntary disruptions in speech fluency and is linked to white matter abnormalities or dopamine hyperactivity in the basal ganglia. Recently, stuttering has been shown to link to point mutations in a gene involved in the lysosomal enzyme-targeting pathway (i.e., GNPTAB), though it remains unclear how such a mutation might relate to the stuttering phenotype. In addition, imaging data suggested that iron might be accumulated in the brain regions involved in speech production, however, the cellular and circuit mechanisms of this finding were unknown. In this study, we used mice engineered with a mutation in the GNPTAB gene found in humans who stutter and found increased iron deposition in the basal ganglia of these mice. Using Perl’s staining method, we stained for iron in age-matched Gnptab-mutant and control mice and analyzed iron deposition based on the intensity of the chemical stain and percent area of deposition. There was an increase in iron deposition in the medial lateral, dorsal lateral, and central striatum of Gnptab-mutant mice when compared to the control animals. Further, these iron deposits localized predominantly with regional astrocytes when Perl’s staining was combined with an astrocyte-specific marker S100ß. Astrocytes, the star-shaped glial cells in the brain, in the striatum were found to be less complex in the Gnptab-mutant mice. There was no cellular loss noted across cell populations, as determined by the quantification of cell bodies in the striatum. These findings support the hypothesis that iron homeostasis is altered in Gnptab-mutant mice and that regional astrocytic morphology differences may have implications for the traditional circuit-modulatory role of these glial cells. Here, we hypothesize a relationship between a missense mutation in a cellular housekeeping mouse Gnptab gene, iron homeostasis, astrocytes, and ultimately the stuttering phenotype that has long remained elusive.
Topic Areas: Language Production, Speech Motor Control