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The Journal of Neuroscience, May 15, 1998, 18(10):3909-3918
Reduced Activity of Hypothalamic Corticotropin-Releasing Hormone
Neurons in Transgenic Mice with Impaired Glucocorticoid Receptor
Function
Ivar
Dijkstra1,
Fred J. H.
Tilders1,
Greti
Aguilera2,
Alexander
Kiss2,
Cristina
Rabadan-Diehl2,
Nicholas
Barden3,
Sharada
Karanth4,
Florian
Holsboer4, and
Johannes M. H. M.
Reul4
1 Graduate School Neurosciences Amsterdam, Department
of Pharmacology, Research Institute Neurosciences Vrije Universiteit,
1081 BT Amsterdam, The Netherlands, 2 Section on Endocrine
Physiology, Developmental Endocrinology Branch, National Institute
of Child Health and Human Development, National Institutes of Health,
Bethesda, Maryland 20892, 3 Neuroscience, Centre
Hospitalier de l'Université Research Centre and Department of
Physiology, Laval University, Québec, Canada G1V 4G2, and
4 Max Planck Institute of Psychiatry, Department of
Neuroendocrinology, Section Neuroimmunoendocrinology, D-80804 Munich,
Germany
Loss of central glucocorticoid receptor (GR) function is thought to
be involved in the development of neuroendocrine and psychiatric disorders associated with corticotropin-releasing hormone (CRH) hyperactivity. The possible causal relationship between defective GR
function and altered activity of CRH neurons was studied in transgenic
mice (TG) expressing antisense RNA against GR. Immunocytochemical studies showed significant reductions in CRH immunoreactive neurons in
the paraventricular nucleus (PVN) and in CRH and vasopressin (AVP)
stores in the external zone of the median eminence. Concomitantly, stimulus-evoked CRH secretion from mediobasal hypothalami of TG mice
in vitro was reduced significantly. However, CRH mRNA
levels in the PVN of TG mice were marginally lower than those in
wild-type (WT) mice. 125I-CRH binding autoradiography
revealed no differences between WT and TG animals in any of the brain
regions that were studied. Basal plasma corticosterone (cort) levels
and 125I-CRH binding, CRH-R1 mRNA, POMC mRNA,
and POMC hnRNA levels in the anterior pituitary gland were similar in
WT and TG mice. Intraperitoneal injection of interleukin-1 (IL-1)
increased plasma cort levels, CRH mRNA in the PVN, and anterior
pituitary POMC hnRNA similarly in WT and TG mice. The injection of
saline significantly reduced anterior pituitary CRH-R1 mRNA
levels in WT mice, but not in TG mice, whereas IL-1 produced a
decrease in these mRNA levels in both strains.
The data show that long-term GR dysfunction can be associated with
reduced activity of CRH neurons in the PVN and decreased sensitivity of
pituitary CRH-R1 mRNA to stimulus-induced downregulation. Moreover, the hypothalamic changes observed in this model suggest that
impaired GR function, at least if present since early embryonic life,
does not necessarily result in CRH hyperexpression characteristics of
disorders such as major depression.
Key words:
corticotropin-releasing hormone (CRH); glucocorticoid
receptor (GR); transgenic (TG) mice; IL-1; paraventricular nucleus; HPA axis; CRH receptor
Copyright © 1998 Society for Neuroscience 0270-6474/98/18103909-10$05.00/0
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