Function and mechanism of dopamine receptor D2 (DRD2) in neuroinflammation and behavioral disorders in C57BL/6J mice infected with Toxoplasma gondii TgCtWh6 strain

Toxoplasma gondii (T. gondii) is a globally distributed protozoan parasite, and its chronic infection has been closely associated with various neuropsychiatric disorders. However, the key susceptibility factors and mechanisms by which T. gondii manipulates host behaviors remain insufficiently understood. In this study, based on the comprehensive behavioral analyses including the AI HomeCage platform, and third-generation Nanopore-seq technology, we demonstrated that the T. gondii strain TgCtwh6 induces depression-like symptoms and cognitive impairments in hosts. These effects are linearly correlated with the expression levels of the host dopamine receptor D2 (DRD2). Furthermore, the behavioral abnormalities can be alleviated by treatment with the DRD2 agonist bromocriptine. Both in vivo and in vitro infection models revealed that the downregulation of DRD2 is significantly correlated with neuroinflammation and neuronal injury in the host central nervous system (CNS). Additionally, our findings suggest that the suppression of DRD2 may be regulated by enhanced RNA m⁶A modification following infection and may function through the DRD2/CRYAB/NF-κB signaling axis. These results emphasized the critical role of DRD2 in mediating T. gondii-induced neuroinflammation and neuropsychiatric abnormalities, providing novel insights into the development of therapeutic strategies for neuropsychiatric disorders associated with parasitic infections.