ABSTRACT
Prolonged over-exposure of rats to corticosterone attenuates 5-HT(1A)-receptor-mediated responses in hippocampal CA1 cells through an unknown mechanism, not involving downregulation of 5-HT(1A) receptor expression. We here tested if corticosterone changes 5-HT(1A) receptor function indirectly, by altering hippocampal mRNA expression of NCAM, SGK1, or RGS4, which all modulate 5-HT(1A) receptor function. We found that the expression of none of these candidates was affected by corticosterone treatment.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Corticosterone/pharmacology , Hippocampus/drug effects , Immediate-Early Proteins/drug effects , Neural Cell Adhesion Molecules/drug effects , Protein Serine-Threonine Kinases/drug effects , RGS Proteins/drug effects , Animals , Hippocampus/metabolism , Immediate-Early Proteins/biosynthesis , In Situ Hybridization , Male , Neural Cell Adhesion Molecules/biosynthesis , Protein Serine-Threonine Kinases/biosynthesis , RGS Proteins/biosynthesis , RNA, Messenger/analysis , Rats , Rats, Wistar , Time FactorsABSTRACT
Stress and corticosterone affect, via glucocorticoid receptors, cellular physiology in the rodent brain. A well-documented example concerns corticosteroid effects on high-voltage activated (L type) calcium currents in the hippocampal CA1 area. We tested whether corticosterone also affects calcium currents in another hippocampal area that highly expresses glucocorticoid receptors, i.e. the dentate gyrus (DG). Remarkably, corticosterone (100 nm, given for 20 min, 1-4.5 hr before recording) did not change high-voltage activated calcium currents in the DG, whereas currents in the CA1 area of the same rats were increased. Follow-up studies revealed that no apparent dissociation between the two areas was observed with respect to transcriptional regulation of calcium channel subunits; thus, in both areas corticosterone increased mRNA levels of the calcium channel-beta4 but not the (alpha) Ca(v)1.2 subunit. At the protein level, however, beta4 and Ca(v)1.2 levels were significantly up-regulated by corticosterone in the CA1 but not the DG area. These data suggest that stress-induced elevations in the level of corticosterone result in a regionally differentiated physiological response that is not simply determined by the glucocorticoid receptor distribution and that the observed regional differentiation may be caused by a gene involved in the translational machinery or in mechanisms regulating mRNA or protein stability.
Subject(s)
Calcium Channels, L-Type/metabolism , Corticosterone/pharmacology , Dentate Gyrus/metabolism , Animals , Blotting, Western , Electrophysiology , In Situ Hybridization , In Vitro Techniques , Male , Rats , Rats, WistarABSTRACT
Acute stress and corticosterone enhance 5-HT1A receptor-mediated responses in rat hippocampal CA1 cells within 1-2 h, through a process involving transcriptional regulation of unknown genes. Earlier studies showed that regulation of the 5-HT1A receptor gene cannot explain the functional effects. We here tested the hypothesis that corticosterone targets genes encoding RGS4 or SGK1, which can both affect the 5-HT1A receptor associated Kir channel, thus affecting 5-HT1A receptor function. To this end, the effect of a single corticosterone injection on hippocampal expression of RGS4 and SGK1 mRNAs, measured by in situ hybridization, was studied. Expression of RGS4 or SGK1 mRNA was not affected by the corticosterone injection, neither in the CA1 area nor in other hippocampal subregions. Strikingly, SGK1 mRNA expression was strongly up-regulated in the corpus callosum. We reject, however, the hypothesis that the effect of corticosterone on 5-HT1A responsiveness is mediated via altered RGS4 or SGK1 mRNA expression.
Subject(s)
Corticosterone/pharmacology , Gene Expression Regulation/drug effects , Hippocampus/physiology , Immediate-Early Proteins/genetics , Protein Serine-Threonine Kinases/genetics , RGS Proteins/genetics , RNA, Messenger/genetics , Animals , Hippocampus/drug effects , In Situ Hybridization , Male , RNA, Messenger/drug effects , Rats , Rats, WistarABSTRACT
In this study, we investigated the effects of early life stress on several aspects of serotonin (5-HT) transmission in hippocampus, later on in life. Three-day-old rats were subjected to 24-hour maternal deprivation or control treatment. Maternal deprivation is known to activate the hypothalamo-pituitary-adrenal axis, resulting in increased corticosterone levels at a time-point in life when the axis is particularly insensitive to most stressful stimuli. When these animals had matured to 3 months of age, functional responses to 5-HT as well as 5-HT1A-receptor mRNA expression were examined. Also, indices for hypothalamo-pituitary-adrenal function were studied in the adult state, including hippocampal mRNA expression for the mineralocorticoid and the glucocorticoid receptor. Resting membrane potential of CA1 pyramidal neurons was significantly depolarized in animals earlier subjected to maternal deprivation compared to the controls. Despite this depolarized resting potential, hyperpolarizing responses induced by 5-HT in CA1 pyramidal neurons from deprived compared to non-deprived rats were attenuated. This attenuation in 5-HT response was not accompanied by changes in mRNA expression of the 5-HT1A-receptor. Maternal deprivation was not found to change any of the neuroendocrine parameters investigated once animals had matured. We conclude that maternal deprivation can alter specific aspects of hippocampal 5-HT transmission later on in life, possibly by post-translational modification of the 5-HT1A-receptor or changes in the 5-HT1A-receptor signal transduction pathway.