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Volume 16, Number 21, Issue of November 1, 1996 pp. 6766-6774
Copyright ©1996 Society for Neuroscience

Hippocampal Cell Responses in Mice with a Targeted Glucocorticoid Receptor Gene Disruption

Received June 5, 1996; revised July 26, 1996; accepted Aug. 20, 1996.

Wouter Hesen¹, Henk Karst^{1, 2}, Onno Meijer², Tim J. Cole³, Wolfgang Schmid³, E. Ronald de Kloet², Gunther Schütz³, and Marian Joëls¹

¹ Department of Experimental Zoology, University of Amsterdam, 1098 SM Amsterdam, The Netherlands, ² Division of Medical Pharmacology, Leiden Amsterdam Center for Drug Research, Leiden University, 2300 RA Leiden, The Netherlands, and ³ German Cancer Research Institute, DE-69009 Heidelberg, Germany

Previous studies in rats have shown that cellular properties of hippocampal CA1 neurons are under coordinative control of mineralocorticoid and glucocorticoid receptors (MRs and GRs, respectively). In the present study, we examined electrical properties under conditions of exclusive MR occupation, by using mice with a genetic defect in GRs obtained by homologous recombination techniques. It appeared that in the animals homozygous for the genetic defect, the properties studied, i.e., the voltage-gated Ca currents and responses to serotonin and the cholinergic analog carbachol, resembled the effects observed in adrenalectomized mice, i.e., when no steroid receptors are activated. This may point to the necessity of functional GRs for the development of MR-induced actions. Ca current amplitude and transmitter responses in the heterozygous animals, which combine a reduced amount of GRs in the hippocampus with relatively high circulating levels of corticosterone, were large compared with those in the wild-type controls; this resembles the responses that were observed previously in rats subjected to a very high dose of corticosterone. These findings exemplify the use of GR knockout mice for the study of cellular properties in the brain. Further substantiation of the observations, however, awaits the development of site-specific, inducible GR knockouts.

Key words: calcium currents; serotonin; carbachol; hexokinase; electrophysiology; quantitative enzyme histochemistry

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