Mifepristone Repairs Region-Dependent Alteration of Synapsin I in Hippocampus in Rat Model of Depression

Abstract

Clinical investigations present much evidence that the glucocorticoid receptor (GR) antagonist mifepristone leads to a rapid amelioration of depression. The molecular mechanisms of mifepristone involved in the treatment of depression are not fully understood. Depression is associated with hippocampal plasticity, for which increased excitatory amino acid (EAA) release in CA3 induced by chronic stress is responsible, and glucocorticoids have a permissive role and act synergistically with EAAs in producing neuronal damage. Moreover, glucocorticoids increase synapsin I, which has a key role in the release of neurotransmitter, including EAAs. Hereby, we hypothesize that major depression involves synapsin I alteration and that mifepristone blocks this alteration. In the present study, we observed both the expression of hippocampal synapsin I and depression-associated behavior in a rat model of depression induced by chronic unpredictable mild stress (CUMS). The result showed that a region-dependent synapsin I alteration occurs in the rat hippocampus after 21 days of CUMS, that is, it increases in dentate gyrus (DG)/CA3 and decreases in the CA1 region. Correlation analysis indicated that the decrease of synapsin I in CA1 is highly correlated with the increase in the DG/CA3 subfield. Simultaneously, the region-dependent alteration of synapsin I is correlated with depression-associated behaviors. Both the alteration of synapsin I and the depression-associated behavior were rapidly restored after treatment with mifepristone for 1 week. The result suggests that the molecular mechanism underlying the treatment of depression with mifepristone is associated with the rapid repair of the synaptic alteration.

Glucocorticoid Receptor Blockade Normalizes Hippocampal Alterations and Cognitive Impairment in Streptozotocin-Induced Type 1 Diabetes Mice

“…Whether mifepristone's prevention and/or reversal of the disturbances caused by diabetes is directly on hippocampal astrocytes, neurons, and proliferative cells, or by changing its surroundings (ie their inputs) requires further investigation. It is worth noting that 4 days mifepristone treatment can affect not only the functioning of these cells (present study, Karst and Joëls, 2007;Wu et al, 2007;Mayer et al, 2006;Wong and Herbert, 2005), but also the innervating projections from other brain regions (Witter, 2007). Moreover, in the present study, we reported that reversion of hippocampal alterations takes place in the face of hypercorticism.…”

Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression

“…32 The necessity of corticosterone in CMS-induced depression is further demonstrated by the lack of depressive symptoms in adrenalectomized mice. This finding, together with the results of a recent study demonstrating that administration of the glucocorticoid receptor antagonist mifepristone (RU-486) abolished CMS-induced behavioral and neural alterations, 67 indicate that at least in the CMS model, glucocorticoids secretion is causally related to the development of the depressive symptoms. This conclusion is further strengthened by the finding that chronic corticosterone administration resulted in depressive symptoms similar to those displayed by mice that were exposed to CMS.…”

Involvement of norepinephrine and serotonin system in antidepressant-like effects of hederagenin in the rat model of unpredictable chronic mild stress-induced depression

“…In parallel, chronic treatment with ESC, as well as with HG, at 5 mg/kg ameliorated the anxiety/ depression-like behaviors caused by UCMS exposure, including increase of locomotor activity in the OFT, percentage of time spent in open arm in the EPM to some extent. Anhedonia, one of the core symptoms of depression, has been defined as decreased responsiveness to rewards, which was measured in depressive animals by decreased preference of sucrose solution (Willner, 1997;Willner et al, 1987;Wu et al, 2007). The depressive state induced by UCMS is associated with anhedonia and despairing behaviors that can be assessed in the SPT and FST, respectively.…”