Flattening the glucocorticoid rhythm causes changes in hippocampal expression of messenger RNAs codingstructural and functional proteins: Implications for agingand depression

Abstract

Subtle changes in glucocorticoid levels, including a flattening of the diurnalrhythm with raised nadir, are prevalent, being characteristic of both aging and major depression. Both these conditions are also associated with deficits in hippocampally mediated cognitive functions.We hypothesized that this profile of glucocorticoid levels causes structural and functional changes in the hippocampus, which in turn mayengender cognitive deficits. We implanted slow-release corticosterone pellets into adrenally intact adult male rats to produce a flattenedglucocorticoid rhythm with levels clamped midway between the normalnadir and zenith. Using density profile analysis we measuredhippo campalexpression of messenger RNAs encoding structural and functional proteins. In rats with a flattened glucocorticoid rhythm, the expression of the mRNA coding for microtubule associated protein-2b (MAP2b) was reduced in CA3 relative to sham-operatedcontrols, but unchanged in dentate gyrus and CA1. In contrast, the expression of the mRNA coding the alpha subunit of calcium-calmodulin dependent kinase (CAMKIIa) was reduced in dentate gyrus in animals with a flattened glucocorticoid rhythm, but unchangedin CA3. The expression of the mRNA coding the synaptic vesicle protein synaptophysin was unchanged in both CA3 and dentate gyrus.The data indicate that a flattening of the normal diurnalglucocorticoid rhythm decreases the hippocampalexpression of mRNAs codingkey structural and functional proteins, and does so in a regionally selective manner. The data may have relevance for cognitive deficitscharacteristic of aging and depression. © 2003 American College of Neuropsychopharmacology.