Short- and long-term alterations of FKBP5-GR and specific microRNAs in the prefrontal cortex and hippocampus of male rats induced by adolescent stress contribute to depression susceptibility

Abstract

Maladaptation of the hypothalamic-pituitary-adrenal (HPA) axis is involved in susceptibility to depression. Glucocorticoid receptors (GRs) and the co-chaperone protein, FK506 binding protein 51 (FKBP5), play crucial roles in dysfunction of the HPA axis. Further, certain microRNAs (miRNAs), such as miR-124a and miR-18a, which could reduce GR protein expression, contribute to affective disorders, while miR-511 as a regulator of FKBP5 is involved in an increased risk of depression. However, the short-term and persistent impacts of adolescent stress on miR-124a, miR-18a, and miR-511 expressions in the brain are unknown. Using depression models of chronic unpredictable mild stress (CUMS) or dexamethasone administration of adolescent rats, the authors of the present study probed the depressive-like behaviors, GR and FKBP5 expressions, and miR-124a, miR-18a, and miR-511 expressions in the prefrontal cortex and hippocampus. The GR antagonist RU486 was used as intervention. The results revealed that both CUMS and dexamethasone administration in the adolescent period resulted in anhedonia, altered locomotor behaviors, anxiety, and cognitive impairment. A remarkable decrease in GR expression, and increase in FKBP5, miR-124a, and miR-18a expressions were detected in the prefrontal cortex and hippocampus of adolescent rats. Furthermore, the similar long-term changes on behaviors and expressions of GR, FKBP5 and GR-related microRNAs were found in the adult rats following CUMS and dexamethasone treatment in adolescence. However, reduced miR-511 expression was observed only in the prefrontal cortex of adult rats exposed to adolescent CUMS or dexamethasone administration. These data suggested that the downregulation of GR, upregulation of FKBP5, miR-124a, and miR-18a in the prefrontal cortex and hippocampus, and downregulation of miR-511 in the prefrontal cortex were relevant to depressive-like behaviors.