DUSP6 loss enhances dopamine secretion and modulate neurodevelopment in ADHD iPSC-derived dopaminergic neurons

Although the gene DUSP6 has been implicated as a risk gene for attention deficit hyperactivity disorder (ADHD) in recent GWAS studies, its functional role in the aetiology of the condition remains poorly understood. DUSP6 is reported to regulate dopaminergic neurotransmission by decreasing available synaptic dopamine, suggesting a potential mechanism by which DUSP6 may confer risk to ADHD. In this study, we employed CRISPR-Cas9 to generate isogenic iPSC lines from an individual with ADHD, including heterozygous and homozygous DUSP6 knockouts alongside the parental control. These iPSC lines were differentiated into dopaminergic neurons and assessed at both cellular, and transcriptomic levels. We observed significant increase in extracellular dopamine in proportion to DUSP6 gene dosage, with greater elevation in homozygous compared to heterozygous knockouts. RNA sequencing further supported this finding, showing that DUSP6-knockout increased expression of genes regulating dopamine secretion and synaptic processes critical for dopaminergic system. Beyond dopamine signalling, transcriptomic changes implicated DUSP6 in neurodevelopmental biological mechanisms, essential to the development of ADHD. Furthermore, we identified significant overlaps between DUSP6-regulated genes and those associated with major depression, bipolar disorder, and schizophrenia, suggesting shared genetic pathways potentially influenced by DUSP6. This study provides mechanistic insights into the role that DUSP6 could potentially play in the aetiology of ADHD and its broader implications across related neuropsychiatric conditions.