It has become increasingly clear that the increase in corticosteroid levels, e.g. after a brief stressor induce molecular and cellular changes in brain, including the hippocampal formation. These effects eventually result in behavioral adaptation. Prolonged exposure to stress, though, may lead to mal-adaptation and even be a risk factor for diseases like major depression in genetically predisposed individuals. We conducted a series of experiments where changes in brain function were examined after 3 weeks of unpredictable stress. After unpredictable stress, inhibitory input to neurons involved in the hypothalamus-pituitary-adrenal (HPA) axis regulation was suppressed, which may dysregulate the axis and lead to overexposure of the brain to glucocorticoids. Furthermore, glutamate transmission in the dentate gyrus (DG) was enhanced, possibly through transcriptional regulation of receptor subunits. Combined with enhanced calcium channel expression this could increase vulnerability to cell death. Neurogenesis and apoptosis in the dentate were diminished. Synaptic plasticity was suppressed both in the dentate and CA1 area. Collectively, these effects may give rise to deficits in memory formation. Finally, we observed reduced responses to serotonin in the CA1 area, which could contribute to the onset of symptoms of depression in predisposed individuals. All of these endpoints provide potential targets for novel treatment strategies of stress-related brain disorders.

Rises in corticosteroid levels, e.g. after acute stress, impair synaptic plasticity in the rat hippocampus when compared with the situation where levels are basal, i.e. under rest. We here addressed the question whether basal and raised levels of corticosterone affect synaptic plasticity similarly in animals that experienced chronic stress prior to corticosterone application. To this end, rats were exposed to a 21-day variable stress paradigm. Synaptic plasticity was examined in vitro in the dentate gyrus and CA1 hippocampal region, 24 h after exposure to the last stressor, i.e. when corticosterone levels are basal (low). First we observed that long-term potentiation was greatly impaired in both CA1 and dentate gyrus after 3 weeks of exposure to variable stress, when recorded under conditions where plasma corticosterone levels are low. Second, administration of 100 nm corticosterone in vitro reduced synaptic plasticity in CA1 of control rats, but induced no further impairment of synaptic plasticity in chronically stressed rats. Third, in the dentate gyrus, corticosterone incubation did not affect synaptic plasticity in slices from both control and stressed animals. We conclude that: (i) exposure to chronic variable stress per se reduces synaptic plasticity both in CA1 and dentate gyrus; and (ii) acute rises in corticosterone level induce no additional impairment of synaptic plasticity in the CA1 region of chronically stressed rats. It is tempting to speculate that the stress-induced reduction of hippocampal efficacy provides a cellular substrate for cognitive deficits in hippocampus-dependent learning tasks seen after prolonged exposure to stressful events.

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Calcium entering the cell via different routes, e.g.,N-methyl-D-aspartate (NMDA) receptors or voltage-dependent calcium channels (VDCCs), plays a pivotal role in hippocampal synaptic potentiation. Since corticosteroid hormones have been reported to enhance calcium influx through VDCCs, one may predict that these hormones facilitate hippocampal synaptic efficacy. Surprisingly, though, stress and corticosteroids have so far been found to reduce synaptic potentiation. Here, we addressed this apparent paradox and examined synaptic potentiation in the CA1 area of hippocampal slices from mice with low basal corticosterone levels 1--4 h after a brief in vitro administration of corticosterone. Nifedipine and APV were used to isolate NMDA receptor-mediated and VDCC-mediated long-term potentiations (LTPs), respectively. We report that corticosterone facilitates synaptic potentiation that depends on activation of VDCCs while impairing synaptic plasticity that is mediated by NMDA receptor activation. The glucocorticoid-receptor (GR) antagonist RU 38486 blocked both the effects of corticosterone. These results indicate that the net effect of corticosteroid hormones on synaptic plasticity is determined by the balance between different types of potentiation, a balance that may be region specific and depends on the experimental conditions. We speculate that these opposite effects on synaptic efficacy are involved in the bidirectional modulation of cognitive performance by corticosteroid hormones.