NR2B overexpression leads to the enhancement of specific protein phosphorylation in the brain

n-methyl-d-aspartate receptors (NMDARs) are highly expressed in the central nervous system (CNS) including the cerebral cortex, and it has been found that they contribute significantly to the processes of learning and memory. Dysfunctions of NMDARs are implicated in many neurological disorders. To further investigate the specific role of the NR2B subunit of NMDARs in brain functions, we have examined differences in gene expression in the cerebral cortex between NR2B transgenic mice and their wild-type littermates using the DNA microarray. Total of 179 differentially expressed genes were identified, including genes involved in ion channel activity and/or neurotransmission, signal transduction, structure/cytoskeleton, transcription, and hormone/growth factor activity. Signal pathway analysis has indicated that multiple pathways were involved in this process, especially the Mitogen-activated protein kinases/Extracellular signal-regulated kinases (MAPK/ERK) pathway. The phosphorylation levels of ERK and cAMP response element-binding protein (CREB), and the mRNA levels of CREB target genes (C-Fos and Nr4a1) were significantly upregulated in the cerebral cortices of NR2B transgenic mice compared to their wild-type littermates. Our study suggested that a chronic increase of NMDARs activation by NR2B overexpression in the forebrain may enhance the protein serine/threonine phosphorylation levels of MAPK/ERK-CREB and thereby regulated their signaling pathway.