Microarray analysis of gene expression changes in the brains of NR2B-induced memory-enhanced mice

Abstract

Glutamate N-methyl-D-aspartate (NMDA) receptors play a pivotal role in different forms of memory. The dysfunction of NMDA receptors contributes to the pathology of central nervous system (CNS) disorders. To further investigate the role of the NMDA receptors in brain processes, we analyzed and compared the gene expression profiles in the hippocampus of NR2B overexpression-induced memory-enhanced mice (Tg mice) with those of their wild-type littermates. Results reveal that 249 genes, which are mainly involved in neurotransmission, signal transduction, cytoskeletal structure, hormone activity, and transcription, were significantly affected in Tg mice. Interestingly, the intracellular calcium channel proteins ryanodine receptor (RyR) 1 and 3, as well as functionally related proteins such as the histidine-rich calcium-binding protein and triadin 2, were upregulated. The Homer-1c protein was also increased in Tg mice and formed a complex with the RyR protein in the mouse brain, suggesting that Homer-1c is an important modulator in both intracellular calcium signaling and overall neuronal signaling by simultaneously interacting with the NMDA receptors and RyR. Western blot and real-time PCR results show that the expression of phospho-CREB, c-fos, and the immediate-early genes Egr2 and Egr4 were also upregulated in Tg mice. The current study demonstrates that a chronic increase in the activation of NMDA receptors affected the expression of a large number of genes and may provide important clues for a better understanding of the molecular mechanism of NMDA receptor-modulated learning and memory, as well as of CNS disorders.