Hippocampal dentate gyri proteomics reveals Wnt signaling involvement in the behavioral impairment in the THRSP-overexpressing ADHD mouse model

Proteomics in the hippocampal dentate gyri reveal that behavioural impairments in THRSP-overexpressing mice could be regulated by Wnt signalling. Children with attention-deficit/hyperactivity disorder (ADHD) often struggle with impaired executive function, temporal processing, and visuospatial memory, hallmarks of the predominantly inattentive presentation (ADHD-PI), subserved by the hippocampus. However, the specific genes/proteins involved and how they shape hippocampal structures to influence ADHD behavior remain poorly understood. As an exploratory tool, hippocampal dentate gyri tissues from thyroid hormone-responsive protein overexpressing (THRSP OE) mice with defining characteristics of ADHD-PI were utilized in proteomics. Integrated proteomics and network analysis revealed an altered protein network involved in Wnt signaling. Compared with THRSP knockout (KO) mice, THRSP OE mice showed impaired attention and memory, accompanied by dysregulated Wnt signaling affecting hippocampal dentate gyrus cell proliferation and expression of markers for neural stem cell (NSC) activity. Also, combined exposure to an enriched environment and treadmill exercise could improve behavioral deficits in THRSP OE mice and Wnt signaling and NSC activity. These findings show new markers specific to the ADHD-PI presentation, converging with the ancient and evolutionary Wnt signaling pathways crucial for cell fate determination, migration, polarity, and neural patterning during neurodevelopment. These findings from THRSP OE mice support the role of Wnt signaling in neurological disorders, particularly ADHD-PI presentation.

Automated summary

Proteomics analysis revealed that Wnt signaling may regulate the behavioral impairments in THRSP-overexpressing mice in the hippocampal dentate gyri. Children with ADHD-PI often suffer from impaired executive function, temporal processing, and visuospatial memory, which are controlled by the hippocampus. However, the specific genes/proteins involved and how they influence ADHD behavior in the hippocampus are still not well understood. Proteomics and network analysis showed dysregulated Wnt signaling affecting hippocampal dentate gyrus cell proliferation and neural stem cell activity.