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.

Abstract

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. 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. To induce the depression model, Wild-Type (WT), ANXA1 Knockout (KO), and FPR2/3 KO mice were exposed to oral administration of CORT for 28 days dissolved in drinking water. Following this, histological, biochemical and behavioural analyses were performed. 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 a higher expression of Brain-Derived Neurotrophic Factor (BDNF), phospho-ERK, cAMP response element-binding protein (pCREB) and a decrease in Serotonin Transporter Expression (SERT) compared to WT(CORT+) mice. 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.