Role of MSK in chromatin remodelling underlying stress-induced transcriptional induction in dentate gyrus granule neurons and behavioural adaptation

Stress is part of everybody's every day life. We need to respond appropriately to stressful events and normally we learn from them to cope better the next time they are imposed on us. These learning and adaptation processes are taking place in the brain. These processes must work properly as improper functioning can cause illness such as depression and anxiety. However, we currently do not fully know how the brain learns from stressful events. We have recently discovered that after stress certain molecular processes ('histone modifications') are taking place in the nucleus of nerve cells which we think are crucial for the expression of certain genes necessary for the adaptation of these cells to the stressful event. These processes are triggered by certain hormones which are released within the brain or by hormone glands and that bind to receptors on the cell surface or inside these cells. The hormones do not trigger the molecular processes in the nucleus directly but do so via so-called signalling molecules. Our proposal aims to identify those signalling molecules and determine how these molecules act in order to gain insight into how nerve cells 'learn' from stressful events.

Exposure to a psychologically stressful event requires, in addition to generation of the acute stress response, cognitive processing in order to learn from it and thus to be able to respond more appropriately in case of future recurrences. Insight into the molecular and cellular mechanisms underlying stress coping and stress processing in the brain is clearly vital for the development of strategies to improve the quality of life of humans and animals. We have found that, in the case of a learned behavioural response to stress in rats and mice, this process involves chromatin remodelling (driven by phosphorylation and subsequent acetylation of histone H3) to induce transcriptional activation in dentate gyrus neurons in the limbic brain which is mediated through concurrent stimulation of glucocorticoid receptor (GR) and NMDA receptor (NMDA-R)/MAPK/ERK signalling mechanisms. Moreover, signalling to the chromatin was disrupted by genetic deletion of the principal histone H3 kinase Mitogen- and Stress-activated Kinase (MSK). Of relevance, MSK is also a potent CREB kinase. We hypothesise that MSK is a key mediator of psychological stress-activated GR and NMDA/MAPK/ERK signalling to the chromatin that results in transcriptional activation and encoding of memory of the stressful event. In these processes, (1) GR and ERK concertedly activate MSK which then phosphorylates histone H3 (P-H3); (2) also, the activated MSK through phosphorylation of CREB and subsequent recruitment of histone acetyl transferase (HAT) activity indirectly drives the acetylation of P-H3 (PAc-H3); and (3) the PAc-H3-evoked chromatin remodelling results in activation of gene expression that is critical for the memory formation associated with the stressful event. To test this hypothesis we will use state-of-the-art inducible tissue-specific mutant mice and lentiviral-driven RNA interference technology in combination with neuroanatomical, immunohistochemical and behavioural analyses.