Novelty stress induces phospho-acetylation of histone H3 in rat dentate gyrus granule neurons through coincident signalling via the N-methyl-D-aspartate receptor and the glucocorticoid receptor: relevance for c-fos induction.

The hippocampus plays an important role in novelty detection, stress-related adaptation and learning and memory. However, it is unknown whether the response to novelty in the hippocampus involves induction of chromatin remodelling events known to be associated with transcriptional regulation. Here, we examined whether exposure to a novel environment, a mild psychological stressor, would affect the number of phospho-acetylated histone H3-positive [P(Ser10)-Ac(Lys14)-H3+] neurons in the rat hippocampus. We show that: (i) the stressful situation induced a marked increase in the number of P(Ser10)-Ac(Lys14)-H3+ neurons, specifically in the dentate gyrus; (ii) the stress-induced rise in P(Ser10)-Ac(Lys14)-H3+ neurons occurred in the dentate gyrus throughout the rostro-caudal axis of the hippocampus, but they were exclusively located in the middle and superficial aspects of the granular cell layer of the upper blade of the dentate gyrus; (iii) antagonism of NMDA or glucocorticoid receptors, but not antagonism of mineralocorticoid receptors or inhibition of nitric oxide synthesis, attenuated the stress-induced response; (iv) combined blockade of NMDA and glucocorticoid receptors ablated the stress-induced histone modification response; (v) moreover, this combined blockade also abolished the induction of the P(Ser10)-Ac(Lys14)-H3-associated gene product c-fos after stress; (vi) administration of corticosterone to unstressed rats did not affect histone H3 phospho-acetylation. Thus, novelty stress induces chromatin remodelling and c-fos induction in mature dentate neurons through concurrent signalling via the NMDA receptor and the glucocorticoid receptor.