hiPSC-derived cortical neurons from ADHD individuals reveal dysregulated glutamatergic development.

Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder characterised by inattention, hyperactivity, and impulsivity, significantly impacting life quality and mortality. It is among the most heritable neuropsychiatric disorders, yet its aetiology remains unclear, hindering the development of novel medications. Previously, research has primarily focused on the dopaminergic and noradrenergic systems using animal models. However, there is growing evidence for a role of the glutamatergic system in ADHD pathomechanisms, and a translational failure between pre-clinical animal models and human clinical trials. We therefore established and characterised a functional cortical neuronal model using human induced pluripotent stem cells (hiPSCs) to investigate glutamatergic development in healthy controls and adult ADHD patients. hiPSCs from healthy controls and ADHD patients showed no difference in their capacity to form cortical neurons (CNs). However, CNs from ADHD patients showed an altered developmental pattern, characterised by changes in extracellular glutamate and decreased transcription of NEUN, PSD95 and EEAT2. Moreover, a significant ~50% reduction in vGLUT2 transcription was observed at multiple time points, suggesting a robust cellular disease endophenotype which might be suitable for future drug screening. Lastly, calcium imaging analysis revealed decreased synaptic signalling strength and frequency, indicating a hypoactive phenotype. In summary, we were able to establish a functional hiPSC-derived cortical neuronal model to investigate ADHD pathomechanisms, which revealed impaired glutamatergic development in ADHD individuals. Our results suggest that the glutamatergic system should also be a target for future drug development.