Biology subjects

Millwater, M.

Publications and source records attributed to Millwater, M..

4 recordsLinked to original sources

bioRxiv2025

Non-vocal motor deficits in a transgenic mouse model linked to stuttering disorders

Stuttering is a neurodevelopmental disorder characterized by involuntary disruptions in speech. In addition, non-vocal motor impairments are reported in some individuals who stutter. Although its precise cause remains unknown, mutations in lysosomal trafficking proteins (such as GNPTAB) have been identified in a subgroup of people who stutter. To understand the functional significance of these mutations, transgenic Gnptab mice have been developed, and as expected, these mice exhibit vocal deficits throughout developmental stages. However, whether these mice also display non-vocal motor impairments is unknown. Our data reveal deficits in the breathing, locomotion, and grooming behaviors of the Gnptab mouse model, outlining a broader phenotype linked to GNPTAB mutations in stuttering. These findings suggest that lysosomal dysfunction may disrupt astrocyte-regulated motor circuits, affecting both vocal and non-vocal rhythmic behaviors that are central to stuttering neurophysiological symptoms.

genetics↗

bioRxiv2025

Iron dysregulation in mice engineered with a mutation associated with stuttering

Stuttering is a neurodevelopmental disorder characterized by involuntary disruptions in the normal fluency and timing of speech. Recently, stuttering has been related to specific point mutations in GNPTAB, a gene involved in lysosomal enzyme-targeting pathways, though it remains unclear how such a mutation might cause the stuttering phenotype. Herein, we studied mice engineered with the mutation in the Gnptab gene found in humans who stutter and found increased iron deposition in the basal ganglia of these mice. Further, we found these iron deposits localized predominantly with regional astrocytes when Perls stain was combined with an astrocyte-specific marker. Reducing iron deposition in the brain with iron chelation therapy improved vocalization symptoms in Gnptab-mutant mice. Our data suggest a relationship between the Gnptab mutation, iron homeostasis in astrocytes, and the stuttering phenotype, for which the underlying mechanisms remain to be elucidated.

cell biology↗

bioRxiv2024

Morphological deficits of glial cells in a transgenic mouse model for developmental stuttering

Vocal production involves intricate neural coordination across various brain regions. Stuttering, a common speech disorder, has genetic underpinnings, including mutations in lysosomal-targeting pathway genes. Using a Gnptab-mutant mouse model linked to stuttering, we examined neuron and glial cell morphology in vocal production circuits. Our findings revealed altered astrocyte and microglia processes in these circuits in Gnptab-mutant mice, while control regions remained unaffected. Our results shed light on the potential role of glial cells in stuttering pathophysiology and highlight their relevance in modulating vocal production behaviors.

cell biology↗

bioRxiv2023

Whole-brain analysis of CO2 chemosensitive regions and identification of the retrotrapezoid and medullary raphe nuclei in the common marmoset (Callithrix jacchus)

Respiratory chemosensitivity is an important mechanism by which the brain senses changes in blood partial pressure of CO2 (PCO2). It is proposed that special neurons (and astrocytes) in various brainstem regions play key roles as CO2 central respiratory chemosensors in rodents. Although common marmosets (Callithrix jacchus), New-World non-human primates, show similar respiratory responses to elevated inspired CO2 as rodents, the chemosensitive regions in marmoset brain have not been defined yet. Here, we used c-fos immunostainings to identify brain-wide CO2-activated brain regions in common marmosets. In addition, we mapped the location of the retrotrapezoid nucleus (RTN) and raphe nuclei in the marmoset brainstem based on colocalization of CO2-induced c-fos immunoreactivity with Phox2b, and TPH immunostaining, respectively. Our data also indicated that, similar to rodents, marmoset RTN astrocytes express Phox2b and have complex processes that create a meshwork structure at the ventral surface of medulla. Our data highlight some cellular and structural regional similarities in brainstem of the common marmosets and rodents.

physiology↗