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 ß2m-/-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.

CD4+CD25+Foxp3+ regulatory T cells prevent the development of Th1 immune response by inhibition of dendritic cell function during the early stage of Plasmodium yoelii infection in susceptible BALB/c mice.

Protective immunity against murine malaria infection depends largely on the establishment of effective Th1 immune response during the early stages of infection. Experimental data suggest that the death of Plasmodium yoelii 17XL (Py 17XL) susceptible BALB/c mice results from the suppression of Th1 immune response mediated by CD4+CD25+Foxp3+ regulatory T cells (Tregs). However, the mechanism by which Tregs regulate Th1 immune response is poorly understood. Since immunity is initiated by dendritic cells (DCs), we analysed DC responses to Py 17XL in control and Treg-depleted BALB/c mice. Myeloid DC proliferation, phenotypic maturation and interleukin-12 (IL-12) production were strongly inhibited in control BALB/c mice. In contrast, plasmacytoid DC proliferation and IL-10 production were strongly enhanced in control BALB/c mice. In-vivo depletion of Tregs resulted in significantly reversed inhibition of DC response, which may contribute to the establishment of Th1 immune response, indicating that Tregs contribute to the suppression of Th1 immune response during malaria. These findings suggest Tregs contribute to prevent Th1 immune response establishment during the early stage of Py 17XL infection by inhibiting DC response.