Ahi1 Modulates Glucocorticoids Receptor Signaling In Depressive Behaviors

Major depression disorder(MDD)is one of the most prevalent forms of Stress-related psychiatric disorders,which have been reported to associate with alteration in hypothalamic-pituitary-adrena(HPA)axis function.Chronic or excessive stressors,either physically or psychologically,can activate the HPA axis by increasing and releasing its end-effectors,glucocorticoid hormones.Also,long-term glucocorticoids treatment can induce depression in humans.Elucidating the neurobiological basis for stress/glucocorticoids-induced depression has therefore become an important topic in medical research.Our studies and others have identified Abelson helper integration site 1 gene(Ahi1)as a susceptibility gene for depression.In the current study,we found that restraint stress or high glucocorticoid treatment decreased the level of Ahi1 protein,which can also be detected in a glucocorticoid-treatment in vitro model.High glucocorticoid level strongly reduced the lever and function of glucocorticoid receptor(GR),which has been implicated in the pathogenesis of depression.Ahi1 was found to interact with GR,and this interaction was decreased by excessive glucocorticoids,which increased the ligand-dependent nuclear translocation of GR.Once dissociated from GR,Ahi1 was subsequently degraded though the ubiquitin-proteasome pathway.The resulting Ahi1 deficiency enhanced the nuclear translocation of GR and decreased the cytoplasmic GR protein level,further amplifying the impairment of the GR function in the hyperactivity HPA axis.We also confirmed that Ahi1 deficiency can affect tyrosine kinase receptor B(TrkB)and brain-derived neurotrophic factor(BDNF)signaling to contribute to depression phenotypes.Consistently,Ahi1 deficient mice showed a low lever of GR in the brain and were insensitive to stress,high glucocorticoid and antidepressant treatments.On the other hand,overexpression of Ahi1 protein inhibited the nuclear translocation of GR and increased its cytoplasmic level.In addition,the decreased expression of AHI1 protein is detected in the blood cells in MD patients and could be reversed by antidepressant treatment.These results suggest that AHI1 is involved in depressionassociated GR signaling in the brain and that its peripheral expression could sever as a biomarker in evaluating the efficiency of antidepressants.