PARP14 Is Increased In The Hippocampus Of Three Mouse Models Of Depression And Its Relationship With Neuroinflammation

BackgroundAs a complex polygenic mental disease,major depressive disorder has destructive impact on both the patients’ quality of life and the global public health.However,due to a series of problems such as the pathological mechanism has not been fully understood and the current clinical antidepressant drugs is incompletely effective and slowly take effect for patients,the comprehensive pathogenesis and new treatment of depression need to be studied urgently.Initially thought to be mutated DNA damage repair protein,PARP family members have now been increasingly shown to play an important role in the pathogenesis of various diseases including neurological diseases.At the same time,the data of our previous research suggest that PARP 14,a member of this protein family,may play a role in the pathogenesis of depression as an important downstream target gene of FTO.PARP14 has also been proved playing critical role in the pathophysiology of several disease and the function of immune cells,but whether PARP 14 plays a role in depression through its effects on the immune system still need further research.ObjectivesThe purpose of this study is to examine whether there are differences in PARP 14 expression levels in depression-related brain regions in mice models of depression and whether PARP 14 may affect the pathogenesis of depression by affecting the inflammatory response of microglia cells.MethodsThree kinds of mice models of depression were established to test whether the expression level of PARP14 is changed in depression-related brain areas by using real-time quantitative PCR and Western-bolt,including chronic restraint model(CRS),chronic unpredictable mild stress model(CUMS),lipopolysaccharide(LPS)model.Immortalized microglia cell line BV2 were cultured and simulated by lipopolysaccharide to analyze the change of PARP14 expression.At the cellular level,the inflammatory response of BV2 to lipopolysaccharide treatment after PARP14 overexpression,knockdown and PARP 14 inhibitor treatment by analyzes the expression of several pro-inflammatory cytokines and anti-inflammatory cytokines detected by real-time quantitative PCR.ResultsWe found that both mRNA and protein expression of PARP 14 was increased in the hippocampus of three kinds of mice models of depression.Meanwhile,PARP 14 expression level was correlated with the expression level of inflammatory factors in the hippocampus of chronic restraint model.When we used LPS to stimulate mouse immortalized microglia cell line(BV2),and found the expression level of PARP 14 also increased;BV2 cells overexpressing Parp14 expressed more pro-inflammatory cytokines in response to LPS stimulation,while knockdown PARP 14 or PARP 14 inhibitor treated BV2 cells expressed less pro-inflammatory cytokines in response to LPS stimulation.ConclusionThe present study shows that the expression level of PARP14 in the hippocampus of mice models of depression has increased;At the same time,the expression levels of PARP 14 in microglia cells affected the inflammatory response process.All this suggests that stress may let the expression level of PARP 14 in microglia cells and then promoting the increase of neuroinflammatory response which finally promotes the pathogenesis of depression.