Role of NR1 subunit of NMDA receptor in etiopathogenesis of schizophrenia: its dysfunction, PET detection and pharmacological targeting
Abstract
Dysfunction of the N-metyl-D-aspartate (NMDA)-type of glutamate receptor has been proposed to play an important role in the etiology of schizophrenia. Polymorphic susceptibility variants in candidate genes of the NMDA receptor have been widely investigated and functionally deficient mutations of the gene (GRIN1) encoding NMDA-NR1 subunit were analyzed in schizophrenic patients.
As the receptor binding studies as well as brain levels of mRNA and protein for NR1 subunit were inconsistent in schizophrenics, the essential role of the NR1 subunit in NMDA-R function has been confirmed by targeted disruptions of the GRIN1 gene in several animal models. Point mutations at positions 481 and 483 led to a significant reduction in the receptor affinity for glycine and in vivo treatment with NR1 antisense ODNs and/or with siRNA to the mRNA NR1 subunit provided another tools to investigate possible diagnostic and therapeutic interventions at the glycine site of the NMDA-NR1 subunit