Functional MHCI deficiency induces ADHD-like symptoms with increased dopamine D1 receptor expression

Inappropriate synaptic development has been proposed as a potential mechanism of neurodevelopmental disorders, including attention-deficit hyperactivity disorder (ADHD). Major histocompatibility complex class I (MHCI), an immunity-associated molecule expressed by neurons in the brain, regulates synaptic development; however, the involvement of MHCI in these disorders remains elusive. We evaluated whether functional MHCI deficiency induced by β2m^-/-Tap1^-/- double-knockout in mice leads to abnormalities akin to those seen in neurodevelopmental disorders. We found that functional MHCI deficiency induced locomotor hyperactivity, motor impulsivity, and attention deficits, three major symptoms of ADHD. In contrast, these mice showed normal spatial learning, behavioral flexibility, social behavior, and sensorimotor integration. In the analysis of the dopamine system, upregulation of dopamine D1 receptor (D1R) expression in the nucleus accumbens and a greater locomotor response to D1R agonist SKF 81297 were found in the functional MHCI-deficient mice. Low-dose methylphenidate, used for the treatment of ADHD patients, alleviated the three behavioral symptoms and suppressed c-Fos expression in the D1R-expressing medium spiny neurons of the mice. These findings reveal an unexpected role of MHCI in three major symptoms of ADHD and may provide a novel landmark in the pathogenesis of ADHD.