PREDICITVE VALIDITY OF THREE HIT THEORY OF DEPRESSION HIGHTLIGHTS THE IMPACT OF EPIGENETIC FACTORS
Tamas Gaszner1, Jozsef Farkas1, Daniel Kun1, Balazs Ujvari1, Laszlo Akos Kovacs1, Nora Furedi1, Balazs Gaszner1
Constantly increasing prevalence of depression encumbers health care system, economy and society. The pathomechanism is still largely unknown also because of the lack of an equivocally accepted animal model. Recently using PACAP heterozygous (HZ) mice we set up a new animal model based on the three hit theory of depression. In this model the coexistence of genetic (mutated PACAP allele), epigenetic (maternal deprivation) and environmental factors (chronic variable mild stress, CVMS) trigger the disease. To test the predictive validity, antidepressant reversal groups were included. Newborn PACAP HZ mice were postnatally maternally deprived vs. controls. Half of adult animals suffered CVMS also and were treated with intraperitoneal fluoxetine or vehicle injections. After behavioral tests, FosB (activational marker), Acetyl-lysine H3 (epigenetic marker) mapping was performed and CRF-FosB immunolabeling was carried in the CeA. Behavioral tests showed the efficacy of treatment. Fourteen of 17 examined limbic brain territories showed significant change, suffered hits in 5 areas, treatment in 2 regions and their interaction in 4 nuclei affected FosB expression. Acetyl-lysin H3 histone labeling revealed that both stress and treatment affect the acetylation of this protein, but maternal deprivation changed the effect of them. The CeA-CRF expression was modified by stress exposure, maternal deprivation and treatment. In summary, genetic background, epigenetic and environmental stressors set a neuronal activity profile in limbic centers including the CeA, that is modified by standard antidepressant treatment. We conclude that our results support the predictive validity of our three hit model in PACAP HZ mice.