Presenter(s)

Ayesha Sheikh

Comments

1:00-1:20, LTC Forum

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Description

Down Syndrome (DS), a prevalent neurodevelopmental disorder, is caused by the triplication of chromosome 21. This genetic anomaly leads to distinct cognitive and motor impairments, often linked to cerebellar dysfunction. Prior studies have reported cerebellar hypoplasia and a reduction in both Purkinje cells (PCs) and granule cells (GCs) in humans and mouse models of DS. Given the cerebellum’s crucial role in motor coordination, its abnormal development likely contributes to the motor deficits observed in individuals with DS. However, the extent to which altered synaptic input to PCs impacts motor deficits remains unclear.This study aimed to investigate cerebellar cytoarchitecture and locomotor function using TcMAC-21 and Dp16 mouse models of DS, compared to euploid controls. TcMAC-21 mice carry a cloned human chromosome 21, while Dp16 mice possess a duplication of the orthologous region on mouse chromosome 16. To assess cerebellar structure, we performed immunohistochemistry (IHC) on sagittal brain sections, specifically focusing on lobules 3 and 9 in both mouse models, using markers for the excitatory neurotransmitter glutamate (VGLUT1 and VGLUT2) and cell-specific markers like GABRA6 to label GCs. Locomotor function was evaluated using the Erasmus Ladder, a task designed to measure gait and adaptive learning.Our findings revealed no motor or adaptive learning deficits in the TcMAC-21 mice, whereas Dp16 mice exhibited significant motor impairments. Moreover, TcMAC-21 mice exhibited a notably reduced thickness in the granule cell layer (GCL) when compared with euploids. Whereas Dp16 mice displayed a differential effect on various regions of the GCL, compared to euploids. These results suggest that different DS models may present distinct neurodevelopmental profiles, offering valuable insight into the variability of motor phenotypes associated with DS. By exploring the molecular and functional alterations in the cerebellum, this study enhances our understanding of DS-related motor deficits and lays the foundation for potential therapeutic interventions.

Publication Date

4-23-2025

Project Designation

Graduate Research

Primary Advisor

Aaron S. Sathyanesan

Primary Advisor's Department

Biology

Keywords

Stander Symposium, College of Arts and Sciences

Institutional Learning Goals

Scholarship; Diversity; Community

Identifying the molecular and behavioral basis of cerebellar dysfunction in TcMAC-21 and Dp16 mouse models of Down Syndrome

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