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

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 oral administration of CORT for 28 days dissolved in drinking water. Following this, 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 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.

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.

Keywords: Depression; annexin A1; corticosterone; formyl peptide receptor 2/3; glucorticoid; hippocampus..