Chronic stress produces sustained elevation of corticosteroid levels which is why

Chronic stress produces sustained elevation of corticosteroid levels which is why it is considered one of the most potent unfavorable regulators of Risedronic acid (Actonel) adult hippocampal neurogenesis (AHN). differentiation of 1 1 to 8 week-old cells in the dentate gyrus of female C57/BL6 mice following exposure to an acute stressor (the Porsolt or forced swimming test). Furthermore we evaluated the effects of the glucocorticoid receptor (GR) antagonist mifepristone around the cell death induced by the Porsolt test. Forced swimming induced selective apoptotic cell death in 1 week-old cells an effect that was abolished by pretreatment with mifepristone. Impartial of its antagonism of Risedronic acid (Actonel) GR Risedronic acid (Actonel) mifepristone also induced an increase in the percentage of 1 1 week-old cells that were AMPA+. We propose that the induction of AMPA receptor expression in immature cells may mediate the neuroprotective effects of mifepristone in line with the proposed antidepressant effects of AMPA receptor potentiators. Introduction Adult neurogenesis takes place in the brain of numerous vertebrates [1] including humans [2]. Under normal physiological conditions this production of new neurons occurs in two brain regions: the subventricular zone of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus. Growing evidence indicates that adult hippocampal neurogenesis (AHN) is crucial for learning and memory [3] [4]. Furthermore alterations in AHN have been implicated in several mood disorders [5] and many antidepressants require AHN to exert their behavioral effects [6]. Numerous external stimuli have been shown to modulate AHN including physical activity [7] environmental enrichment [8] and stress [9]. At the molecular level the rate of AHN is usually regulated by a large variety of signaling molecules including: growth factors such as brain-derived neurotrophic factor (BDNF) [10] insulin-like growth factor I (IGF-I) [11] [12] [13] and vascular endothelial growth factor (VEGF) [14]; neurotransmitters such as glutamate [15] [16]; and pro-inflammatory cytokines [17]. Among the strongest modulators of the rate of AHN are the adrenal corticosteroids. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis resulting in an increase in the levels of circulating glucocorticoids (GCs). In general terms Mouse monoclonal to GFP high GC levels are considered unfavorable regulators of AHN [18] [19] [10] although the complex regulation of AHN by GCs remains poorly understood with many conflicting reports in the literature [20] [21]. The physiological response to acute stress and the accompanying increase in GC levels appear to be adaptative in nature and these events are critical for hippocampal long-term potentiation (LTP) [22] and memory consolidation [23]. However long-term exposure to elevated GC levels triggers a series of alterations that may provoke neurodegeneration in sensitive brain areas [24] [25]. In conjunction with genetic risk factors the inability to return to the basal state following long- term exposure to Risedronic acid (Actonel) high GC levels known as [26] is considered by some authors to be a critical factor in the development of neurodegenerative diseases such as Alzheime?s disease (AD) [27] [28] [29] and of mood disorders like MD [30] [31]. The hippocampus is usually highly sensitive to the effects of both GC and stress and it expresses high levels of corticosteroid receptors of both high (mineralocorticoid receptors MR) and low (glucocorticoid receptors GR) affinity [32] [33]. Chronic exposure to stress induces permanent synaptic and dendritic alterations [34] [35] increases hippocampal glutamate levels [36] [37] and decreases AHN [9]. Thus understanding the molecular mechanisms that regulate responses to stress whether chronic or acute (as studied here) Risedronic acid (Actonel) is particularly important to identify therapeutic targets that modulate these responses and that avoid the damage caused by prolonged exposure to stress. In recent years GR antagonists Risedronic acid (Actonel) have been proposed for the treatment of diverse mood disorders. One such compound with a high degree of clinic relevance is usually mifepristone (RU-486) which has been shown to normalize some of the hippocampal alterations provoked by chronic stress [38].