MOLECULAR CHARACTERIZATION OF GLUTAMATE RECEPTOR EXPRESSION IN BRAIN

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Activity-dependent neural plasticity during development and in the adult is largely mediated by N-methyl-D-aspartate receptor (NR) activation; the natural ligand for this excitatory amino acid receptor is glutamate. The effects of NMDA receptor activation on neural plasticity are largely mediated by the calcium influx, which needs to be regulated since excessive Ca2+ entry kills neurons. For this reason, the regulation of NR channel kinetic properties has important consequences on the signals transduced by these receptors. There are changes in NR function during development in response to activity. We have found that the expression patterns of NR 2B repression and NR 2C activation closely follow the spatial-temporal pattern of granule cell innervation. The down-regulation of NR 2B mRNAs, which occurs after granule cells have migrated into the IGL where they receive afferent inputs, may result from synaptic activity. Thus, different NR subunits may not only function to distinctly modulate synaptic connections in response to activity, but their expression patterns may also be responsive to epigenetic factors. Transcriptional control is a common mechanism directing cell-type specific expression of genes during development and in the adult. In order to begin understanding the complex mechanisms that direct regional-specific transcription of NR genes during neurogenesis and modulate their levels in response to synaptic activity, we have begun to investigate the mechanisms that control expression of the NR2 subunits at the transcriptional level. We have found that transcription of NR 2B transcripts is initiated from different sites, however differential promoter use cannot account for the patterns of NR 2B expression during development since the patterns of initiation were the same in cerebellum and forebrain. Analysis of regulatory regions in transgenic mice reveal that distinct DNA regulatory sequences are required for the neural-specific and developmental regulation of the gene. We have identified an 800bp upstream region that directs neural-specific transcription in transgenic mice but fails to impart the proper developmental down-regulation of the gene in cerebellum. Additional cis-acting sequences residing downstream of the major initiation sites, possibly located within the first intron, were shown to be necessary to repress NR 2B expression during cerebellar development.