Abstract for presentation at 6th World Congress on Stress

Chronic stress is widely regarded as a key risk factor for a variety of diseases, among which are affective disorders. Genetic predispositions are thought to interact with environmental demands such as chronic stress. Using a recently developed novel paradigm for chronic social stress in mice we correlated individual differences in the persisting effects of chronic social stress on hypothalamic-pituitary-adrenal (HPA) function with gene expression changes in the hippocampus. One week after termination of the chronic stress procedure basal corticosterone secretion was markedly increased in the chronic stress group compared to controls. From the chronic stress group (n=120) the animals with the lowest 10% corticosterone secretion were considered resistant to chronic stress exposure, while the animals with the highest 10% were considered vulnerable. After 4 more weeks of single housing, six animals of each subgroup were then selected for expression profiling in laser-microdissected dentate gyrus tissue. Analysis of regulated genes in stress resistant and stress vulnerable animals revealed differentially regulated AMPA receptor subunits, which might affect the susceptibility of an individual to chronic social stress. This hypothesis was tested in a second experiment, where animals were treated with the AMPA receptor enhancer LY451646 or vehicle during the last 4 weeks of chronic stress exposure. Enhanced AMPA receptor function in chronically stressed animals ameliorated the lasting effects of the chronic stress exposure on physiological, neuroendocrine and behavioural parameters. Our data suggest that differences in AMPA receptor function may underlie individual stress vulnerability and support AMPA receptor enhancers as novel potential antidepressants.