REDUCED ACTIVITY OF HYPOTHALAMIC CORTICOTROPIN-RELEASING HORMONE NEURONS IN TRANSGENIC MICE WITH IMPAIRED GLUCOCORTICOID RECEPTOR FUNCTION

Loss of central glucocorticoid receptor (GR) function is thought to be involved in the development of neuroendocrine and psychiatric disorde rs associated with corticotropin-releasing hormone (CRH) hyperactivity . The possible causal relationship between defective GR function and a ltered activity of CRH neurons was studied in transgenic mice (TG) exp ressing antisense RNA against GR. Immunocytochemical studies showed si gnificant reductions in CRH immunoreactive neurons in the paraventricu lar nucleus (PVN) and in CRH and vasopressin (AVP) stores in the exter nal zone of the median eminence. Concomitantly, stimulus-evoked CRH se cretion from mediobasal hypothalami of TG mice in vitro was reduced si gnificantly. However, CRH mRNA levels in the PVN of TG mice were margi nally lower than those in wild-type (WT) mice. I-125-CRH binding autor adiography revealed no differences between WT and TG animals in any of the brain regions that were studied. Basal plasma corticosterone (cor t) levels and I-125-CRH binding, CRH-R-1 mRNA, POMC mRNA, and POMC hnR NA levels in the anterior pituitary gland were similar in WT and TG mi ce. Intraperitoneal injection of interleukin-1 beta (IL-1 beta) increa sed plasma cort levels, CRH mRNA in the PVN, and anterior pituitary PO MC hnRNA similarly in WT and TG mice. The injection of saline signific antly reduced anterior pituitary CRH-R, mRNA levels in WT mice, but no t in TG mice, whereas IL-1 beta produced a decrease in these mRNA leve ls in both strains. The data show that long-term GR dysfunction can be associated with reduced activity of CRH neurons in the PVN and decrea sed sensitivity of pituitary CRH-R-1 mRNA to stimulus-induced downregu lation. Moreover, the hypothalamic changes observed in this model sugg est that impaired GR function, at least if present since early embryon ic life, does not necessarily result in CRH hyperexpression as major d epression.