Genetic dissection of corticosterone receptor function in the rat hippocampus

The hippocampus, a brain structure with a crucial role in learning and memory and an involvement in stress-related neurological or psychiatric disorders, is extremely sensitive to aberrant levels of corticosteroid stress hormones (CORT). We hypothesized that CORT-affected brain disorders are the result of aberrant expression of specific CORT-responsive genes. In order to identify such genes, we have applied several gene expression profiling techniques such as differential display, DNA micro-arrays and in particular the highly sensitive serial analysis of gene expression (SAGE). Using SAGE, a total of 76,790 hippocampal tags were generated which together represent 28,748 unique mRNAs of which 4626 gave a hit with rat sequences in Genbank. By comparing SAGE profiles derived from rat hippocampi treated with different concentrations of corticosteroids, we have identified over 200 CORT-responsive genes with significant differential expression in hippocampus. The identified products include genes that are important for the plasticity of hippocampal neurones such as neural cell adhesion molecules, growth-promoting proteins, genes involved in axogenesis, synaptogenesis and signal-transduction. One novel corticosteroid-responsive gene, classified as Ca2+/calmodulin-dependent protein kinase (CaMK)-VI, exhibited structural resemblance with the family of CaMKs, in particular with that of CaMK-IV. We also identified an alternatively spliced mRNA of this gene encoding a peptide (CaMK-kinase related peptide or CARP) which may function in an autoregulatory feedback loop. These findings suggest a novel mode of operation of the CaMK pathway in control of Ca2+ homeostasis relevant for CORT-related brain disorders.