Alterations in proliferation of neuronal stem cells in Attention-Deficit/Hyperactivity Disorder and Wnt modulation by methylphenidate

As the most common neurodevelopmental and mental disorders around the world, attention-deficit/hyperactivity disorder (ADHD) affects mostly children and adolescents. Both genetic (polygenicity) and environmental variables interplay in the etiology of this disorder. The Wnt signaling pathway, which regulates proliferation and differentiation during neurodevelopment, has been implicated in ADHD. Clinically, ADHD individuals may exhibit delays in structural and functional brain development. Available evidence has proposed that methylphenidate (MPH) treatment can potentially improve these delays. However, the molecular and cellular mechanisms underlying ADHD and the therapeutic targets of MPH are still not completely elucidated. In a pilot investigation, the proliferation of neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs) was significantly lowered in ADHD male patients. Yet, we did not observe any variations in growth rates during the iPSC stage. To extend the earlier results, we increased the sample size to include females and explored if MPH may improve NSC proliferation in ADHD and clarified the role of the Wnt pathway. To do so, iPSC and NSC proliferation of five ADHD patients and five controls was assessed. The results corroborated our previous findings on decreased proliferation in ADHD NSCs. Conversely, ADHD NSC proliferation slightly increased following MPH treatment at 10 nM, which also showed modulatory effects in the Wnt signaling in this group. Interestingly, no increases in proliferation were seen when DKK1 blocked Wnt signaling before MPH treatment. These findings suggest MPH regulates the canonical Wnt pathway and may partially explain ADHD neurodevelopmental abnormalities and MPH-specific benefits.