ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by attentional deficits, hyperactivity, and impulsivity. Despite advances in understanding its genetic and neurobiological underpinnings, comprehensive molecular characterization, particularly at early developmental stages, remains underexplored. This study investigates transcriptomic alterations in the prefrontal cortex (PFC) and striatum (STR) of a postnatal ADHD mouse model induced by 6-hydroxydopamine (6-OHDA), which selectively eliminates dopaminergic neurons. Employing bulk RNA sequencing (RNA-seq) coupled with weighted gene co-expression network analysis (WGCNA), we identified 369 DEGs in the PFC, 493 DEGs in the STR, and 32 modules in WGCNA, uncovering distinct expression profiles associated with ADHD. Functional enrichment analyses identified that PFC-DEGs were involved in PFC development, plasma membrane signaling, and transcriptional regulation. STR-DEGs were associated with STR development, locomotion, extracellular matrix, and response to amphetamine. Notably, we identified significant overlaps between PFC- and STR-DEGs and genes linked to ADHD, autism spectrum disorders (ASD), schizophrenia (SCZ), and bipolar disorder (BD). Co-expression network analyses identified module-specific enrichments related to neurodevelopmental and cognitive functions, highlighting the roles of development, synaptic signaling, metabolism, immunity, and transcription in the pathophysiology of ADHD. These findings demonstrate the intricate gene expressions and co-expression networks underlying ADHD, providing deeper insights into the molecular mechanisms.
