Plasma membrane calcium pump isoform 1 gene expression is repressed by corticosterone and stress in rat hippocampus

Glucocorticoids (GCs) are critical to learning and memory, in large part be cause of their actions in the hippocampus. Chronic high levels of GCs have profound effects on hippocampal structure and function and can even result in irreversible neurodegeneration. Hippocampal GC actions are mediated by i ntracellular receptors that modulate the transcription of specific target g enes. In a screen for genes repressed by GCs in rat hippocampus, we identif ied plasma membrane calcium pump isoform 1 (PMCA1), a plasma membrane calci um ATPase. In Northern blots, PMCA1 was repressed similar to 33% after a hi gh, but not a low dose of the GC, corticosterone (B), suggesting glucocorti coid (but not mineralocorticoid) receptor-mediated repression. Furthermore, in situ hybridization demonstrated that B significantly downregulated PMCA 1 mRNA in all brain regions examined. Repression of PMCA1 was also observed in cultured hippocampal neurons, but only when the cells were in the diffe rentiated state. Stress also repressed PMCA1 expression in hippocampus of a drenal-intact animals, and a clear inverse correlation between B level and PMCA1 mRNA could be discerned. However, other non-B-dependent factors appea red to be involved in the response of PMCA1 to stress because, unlike exoge nous B, cold stress did not repress PMCA1 in brain regions other than hippo campus. Moreover, in the presence of constant B (B-replaced, adrenalectomiz ed animals), cold stress led to increased hippocampal PMCA1 expression. The se observations suggest that repression of PMCA1 represents one molecular m echanism by which corticosteroids regulate Ca2+ homeostasis and hence influ ence neuronal activity. Moreover, other stress-related neurohumoral factors appear to counter the repressive effects of B. Defects in the balance betw een GC-mediated and non-GC-mediated effects on PMCA1 expression may have ad verse effects on neuronal function and ultimately result in irreversible ne uronal damage.