We also appreciate the help of Ana LLorens-Martn in revising the manuscript and Dr Fabio Cafini for critical dialogue of the outcomes. == Footnotes == Competing Passions:Mara Llorens-Martn isn’t aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this manuscript. by pretreatment with mifepristone. Independent of its antagonism of GR, mifepristone also induced an increase in the percentage of 1 1 week-old cells that were AMPA+. We propose that the induction of MTG8 AMPA receptor TCS HDAC6 20b 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 TCS HDAC6 20b 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 regulated by a TCS HDAC6 20b 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 TCS HDAC6 20b circulating glucocorticoids (GCs). In general terms, high GC levels are considered negative 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 high GC levels, known asallostatic load[26], is considered by some authors to be a critical factor in the development of neurodegenerative diseases such as Alzheimes disease (AD) [27] [28] [29], and of mood disorders like MD [30] [31]. The hippocampus is 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) 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 have been proposed for the treatment of diverse mood disorders. One such compound with a high degree of clinic relevance is mifepristone (RU-486), which has been shown to normalize some of the hippocampal alterations provoked by chronic TCS HDAC6 20b stress [38] [39]. However, the mode of action of this drug remains a matter of much debate and indeed, it has been proposed that its neuroprotective effects may even be independent of its action as a GR antagonist [40]. In the present study, we evaluated the effects of an acute stress, the forced swim or Porsolt test, on the survival of hippocampal newborn neurons of different ages in order to identify populations particularly sensitive.