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.