The Role of Annexin A1 and Formyl Peptide Receptor 2/3 Signaling in Chronic Corticosterone-Induced Depression-Like behaviors and Impairment in Hippocampal-Dependent Memory

Background: The activity of the hypothalamic-pituitary-adrenal (HPA) axis is commonly dysregulated in stress-related psychiatric disorders. Annexin A1 (ANXA1), an endogenous ligand of formyl peptide receptor (FPR) 2/3, is a member of the family of phospholipid- and calcium-binding proteins with a well-defined role in the delayed early inhibitory feedback of glucocorticoids (GC) in the pituitary gland and implicated in the occurrence of behavioural disorders such as anxiety. Objective: The present study aimed to evaluate the potential role of ANXA1 and its main receptor, as a cellular mediator of behavioural disorders, in a model of corticosterone (CORT)-induced depression and subsequently the possible correlation between the depressive state and impairment of hippocampal memory. Methods: To induce the depression model, wild-type (WT), ANXA1 knockout (KO), and FPR2/3 KO mice were exposed to orally administration of CORT for 28 days dissolved in drinking water. Histological, biochemical and behavioural analyses were performed. Results: FPR2/3 KO and ANXA1 KO mice showed improvement in anxiety and depression-like behaviour compared with WT mice after CORT administration. In addition, FPR2/3 KO and ANXA1 KO mice showed a reduction in histological alterations and neuronal death in hippocampal sections. Moreover, CORT+ FPR2/3 KO and ANXA1 KO, exhibited an higher expression of brain derived neurotrophic factor (BDNF), phospho-ERK, cAMP response element-binding protein (pCREB) and a decrease of serotonin transporter expression (SERT) compared to WT(CORT+) mice. Conclusion: In conclusion, the absence of the ANXA1 protein, even more than the absence of its main receptor (FPR 2/3), was fundamental to the inhibitory action of GC on the HPA axis; it also maintained the hippocampal homeostasis by preventing neuronal damage associated with depression.