Impaired HPA axis and their feedback regulation in SERT knockout mice

Abstract

A polymorphism in 5-HT transporter linked promoter region (5-HTTLPR) is related to the personality and affective disorders. To understand the mechanisms underlying this phenomenon, we used mice with reduced or deficient serotonin transporter (SERT+/− or −/− mice) as a model to investigate the mechanisms mediating their hypersensitivity to stress that is also observed in the humans with short alleles of 5-HTTLPR. We hypothesized that the hypothalamic-pituitary-adrenal (HPA) axis and their feedback regulation are impaired in these mice. The functional, cellular and molecular alterations in the components of HPA axis and the glucocorticoid receptor (GR)-related feedback regulation were characterized during basal and stressed conditions in SERT +/− and −/− mice relative to SERT+/+ mice. Our results revealed that the hypothalamic CRF neurons were suppressed in the basal condition, but was hyper-activated during stress in SERT+/− and −/− mice relative to SERT+/+ mice. The pituitary CRF 1 receptors were up-regulated and sensitized in SERT−/− mice. The basal levels of GR were reduced in the hypothalamus, pituitary and adrenal cortex of SERT+/− and −/− mice. Consistently, dexamethasome-induced attenuation of corticosterone was blunted in SERT−/− mice. These data suggest that the stress-induced hyperactivity of the HPA axis in SERT+/− and −/− mice may be due to the reduction of GR-mediated feedback regulation.