Glucocorticoids are secreted from the adrenal gland in very high amounts after stress. In the brain, these stress hormones potently modulate ionic currents, monoaminergic transmission, synaptic plasticity and cellular viability, most notably in the hippocampus where corticosteroid receptors are highly enriched. Here we show that at least some of these actions require DNA binding of glucocorticoid receptor (GR) homodimers.

Recent studies indicated that hyperactivity of the hypothalamopituitary-adrenal system is a considerable risk factor for the precipitation of affective disorders, most notably of major depression. The mechanism by which this hyperactivity eventually leads to clinical symptoms of depression is unknown. In the present animal study, we tested one possible mechanism, i.e., that long-term exposure to high corticosterone levels alters functional responses to serotonin in the hippocampus, an important area in the etiology of depression. Rats were injected daily for 3 weeks with a high dose of corticosterone; electrophysiological responses to serotonin were recorded intracellularly from CA1 pyramidal neurons in vitro. We observed that daily injections with corticosterone gradually attenuate the membrane hyperpolarization and resistance decrease mediated by serotonin-1A receptors. We next used single-cell antisense RNA amplification from identified CA1 pyramidal neurons to resolve whether the functional deficits in serotonin responsiveness are accompanied by decreased expression levels of the serotonin-1A receptor. It appeared that expression of serotonin-1A receptors in CA1 pyramidal cells is not altered; this result was supported by in situ hybridization. Expression of corticosteroid receptors in the same cells, particularly of the high-affinity mineralocorticoid receptor, was significantly reduced after long-term corticosterone treatment. The present findings indicate that prolonged elevation of the corticosteroid concentration, a possible causal factor for major depression in humans, gradually attenuates responsiveness to serotonin without necessarily decreasing serotonin-1A receptor mRNA levels in pyramidal neurons. These functional changes may occur by a posttranscriptional mechanism or by transcriptional regulation of genes other than the serotonin-1A receptor gene itself. mineralocorticoid receptor ͉ glucocorticoid receptor ͉ intracellular recording ͉ single-cell antisense RNA amplification ͉ in situ hybridization C orticosteroid hormones are secreted from the adrenal glands in a circadian pattern (1). In rats, corticosterone circulates in low amounts in the morning and at high concentrations in the evening. Temporary elevations in the level occur after stressful events. Corticosteroids can enter the brain and bind to two intracellular receptor subtypes (2): the mineralocorticoid receptor (MR; K d Ϸ 0.5 nM) and the glucocorticoid receptor (GR; K d Ϸ 5 nM). Because of the difference in affinity, changes in plasma corticosterone concentration alter the relative MR͞GR occupation. Low levels of corticosterone mainly activate brain MRs, whereas high levels at the circadian peak or during stress activate GRs along with MRs (3-5). Electrophysiological studies in CA1 hippocampal neurons, which coexpress MR and GR, have shown that selective activation of corticosteroid receptors alters ion conductances and neurotransmitter responses within 1-2 hours (6). In particular, the membrane hyperpolarization mediated by serotonin-...

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