Genetic dissection of corticosterone receptor function in the rat hippocampus

The hippocampus, a brain structure with a crucial role in learning and memo ry and an involvement in stress-related neurological or psychiatric disorde rs, is extremely sensitive to aberrant levels of corticosteroid stress horm ones (CORT). We hypothesized that CORT-affected brain disorders are the res ult of aberrant expression of specific CORT-responsive genes. In order to i dentify such genes, we have applied several gene expression profiling techn iques such as differential display, DNA micro-arrays and in particular the highly sensitive serial analysis of gene expression (SAGE). Using SAGE, a t otal 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-respon sive genes with significant differential expression in hippocampus. The ide ntified products include genes that are important for the plasticity of hip pocampal neurones such as neural cell adhesion molecules, growth-promoting proteins, genes involved in axogenesis, synaptogenesis and signal-transduct ion. One novel corticosteroid-responsive gene, classified as Ca2+/calmoduli n-dependent protein kinase (CaMK)-VI, exhibited structural resemblance with the family of CaMKs, in particular with that of CaMK-IV. We also identifie d an alternatively spliced mRNA of this gene encoding a peptide (CaMK-kinas e 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. (C) 2001 Elsevier Science B.V. All rights reserved.