Proteomics data reveals Wnt signaling involvement in the hippocampal-dependent behavioral impairment in THRSP-overexpressing attention-deficit/hyperactivity disorder mouse model

Abstract Despite the predominance and high heritability of attention-deficit/hyperactivity disorder (ADHD), its etiology remains unclear. Preclinical and clinical evidence partially implicates impaired limbic system function, particularly in the hippocampus (HPC). Children diagnosed with ADHD often struggle with deficits in executive function, temporal processing, and visuospatial memory, the defining hallmarks of the predominantly inattentive presentation (ADHD-PI), which is subserved by the hippocampus. However, the specific genes/proteins involved and how they shape hippocampal structure to influence ADHD behavior remain poorly understood. As an exploratory tool, hippocampal tissues from a mouse model overexpressing (OE) thyroid hormone-responsive protein (THRSP) with defining characteristics of ADHD-PI were utilized for proteomic analyses. Integrated proteomics and network analysis revealed 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 cell proliferation (BrdU) and neurogenic marker expression (i.e., NEU-N, GFAP), markers of neural stem cell (NSC) activity. In addition, combined exposure to an enriched environment and treadmill exercise could improve behavioral deficits in THRSP OE mice and Wnt signaling and NSC activity.