Psychological stress increases histone H3 phosphorylation in adult dentate gyrus granule neurons: involvement in a glucocorticoid receptor‐dependent behavioural response

Abstract

Chromatin remodelling associated with transcriptional activation of silent genes involves phosphorylation at Serine-10 and acetylation at Lysine-14 in the N-terminal tails of the nucleosomal protein histone H3. We have identified neurons predominantly in the dentate gyrus showing a speckled nuclear immunoreactivity pattern for phosphorylated histone H3 [i.e. P(Ser10)-H3] and phospho-acetylated histone H3 [i.e. P(Ser10)-Ac(Lys14)-H3]. Forced swimming increased the number of P(Ser10)-H3-positive [P(Ser10)-H3+] neurons in the rat and mouse dentate gyrus. Exposure of mice to a predator had a similar effect, but exposing rats to ether vapour or a cold environment evoked no change in the number of P(Ser10)-H3+ dentate neurons, indicating that the effect of stress on histone H3 phosphorylation is stressor-specific. The forced swimming-induced increase in dentate P(Ser10)-H3+ neurons peaked at 8-24 h, was restricted to NeuN+ (i.e. mature) neurons, and occurred mainly in the middle and superficial aspects of the granular cell layer. Moreover, this increase showed stimulus strength dependency (i.e. swimming at 19 degrees C produced a larger increase than swimming at 25 degrees C) and could be blocked by the glucocorticoid receptor (GR) antagonists RU 38486 and ORG 34517. Under these experimental conditions, when the forced swimming-induced behavioural immobility response was determined in a re-test 24 h after the initial forced swim test, striking correlations were observed between the phosphorylation of histone H3 in dentate gyrus granule neurons and the acquired immobility response. Our data indicate that stressful events with a strong psychological component such as forced swimming evoke distinct GR-dependent histone modifications in mature dentate gyrus granule neurons that may participate in the behavioural adaptation of the organism to this event.

Differential Role of Galanin Receptors in the Regulation of Depression-Like Behavior and Monoamine/Stress-Related Genes at the Cell Body Level

“…In view of this complexity, it is difficult to develop valid animal models to study this disorder (Frazer and Morilak, 2005). However, one of the main predisposing factors in development of depression is exposure to traumatic and stressful events (see Kessler, 1997;Bilang-Bleuel et al, 2005), resulting in a dysregulated response of the hypothalamus-pituitaryadrenal (HPA) axis (see Holsboer, 2001). Moreover, depression is often viewed as inability to cope with stress (see Anisman and Zacharko, 1990;Kessler, 1997).…”

“…However, exposure to inescapable swimming may not be sufficiently strong to induce long-lasting depression-like symptoms in the normal rat. Nevertheless, the FST does represent an acute stressful event, since it is associated with a profound increase in adrenocorticotropin and corticosterone levels (Bilang-Bleuel et al, 2002;Rittenhouse et al, 2002), as well as with neurochemical and morphological changes in the hippocampus (Bilang-Bleuel et al, 2005) and prefrontal cortex (Izquierdo et al, 2006). Importantly, the immobility response in the FST can be prevented by glucocorticoid antagonists (Jefferys and Funder, 1987;Korte et al, 1996;Bilang-Bleuel et al, 2005) and various types of antidepressant treatments, including tricyclic antidepressants, monoamine oxidase inhibitors, SSRIs, and NA reuptake inhibitors (see Borsini and Meli, 1988).…”

Acute Stress Responsiveness of the Neurotrophin BDNF in the Rat Hippocampus is Modulated by Chronic Treatment with the Antidepressant Duloxetine

“…However, alternative mechanisms, which, for example, imply an epigenetic control of neurotrophin transcription, could be considered. In fact it has been shown that forced swim stress increases the phosphorylation of histone-3 through a GR-dependent mechanism (Bilang-Bleuel et al, 2005) and posttranslational modifications of histones Stress-dependent BDNF modulation after duloxetine(phosphorylation and/or acetylation) appear to be relevant for neurotrophin transcription, particularly for exons IV and VI (Tsankova et al, 2006).…”

Glucocorticoids act on glutamatergic pathways to affect memory processes

“…These circumstances foster both rapid and delayed (protein-synthesisdependent) synaptic delivery of AMPAR and/or NMDAR subunits [39,40,42,51]. A subsequent and/or additional pathway involves NMDAR-triggering of signaling cascades leading to (epi)genomic changes in gene transcription [14,[73][74][75]80], with at least one of these targets leading to increased probability of glutamate release [80]. In general, rapid effects are mediated by membrane-bound MRs or GRs, whereas delayed genomic effects are mediated by nuclear-localized GRs.…”

“…Specifically, evidence has been presented that glucocorticoid-induced enhancement of memory consolidation (as assessed in a forced swim test) took place through the activation of NMDARs and the downstream mitogen-activated protein kinase (MAPK) pathway, including activation of ERK (extracellular signal-regulated kinase)/MSK (mitogen and stress-activated protein kinase) and transcription factor Elk-1 in the dentate gyrus of the hippocampus [73][74][75]. Activation of this pathway was demonstrated to result in epigenetic changes including enhanced histone acetylation [73][74][75]. These epigenetic mechanisms were only efficient in the presence of activated GRs and they acted in synergy with NMDAR activation [74] (Figure 1e).…”