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. 2000 Nov;1(5):447-51.
doi: 10.1093/embo-reports/kvd088.

Genetic disruption of mineralocorticoid receptor leads to impaired neurogenesis and granule cell degeneration in the hippocampus of adult mice

P Gass  1 , O Kretz, D P Wolfer, S Berger, F Tronche, H M Reichardt, C Kellendonk, H P Lipp, W Schmid, G Schütz
Affiliations

Genetic disruption of mineralocorticoid receptor leads to impaired neurogenesis and granule cell degeneration in the hippocampus of adult mice

P Gass et al. EMBO Rep. 2000 Nov.

Abstract

To dissect the effects of corticosteroids mediated by the mineralocorticoid (MR) and the glucocorticoid receptor (GR) in the central nervous system, we compared MR-/- mice, whose salt loss syndrome was corrected by exogenous NaCI administration, with GR-/- mice having a brain-specific disruption of the GR gene generated by the Cre/loxP-recombination system. Neuropathological analyses revealed a decreased density of granule cells in the hippocampus of adult MR-/- mice but not in mice with disruption of GR. Furthermore, adult MR-/- mice exhibited a significant reduction of granule cell neurogenesis to 65% of control levels, possibly mediated by GR due to elevated corticosterone plasma levels. Neurogenesis was unaltered in adult mice with disruption of GR. Thus, we could attribute long-term trophic effects of adrenal steroids on dentate granule cells to MR. These MR-related alterations may participate in the pathogenesis of hippocampal changes observed in ageing, chronic stress and affective disorders.

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Figures

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Fig. 1. Hippocampal granule cell degeneration in adult MR–/– mice. In Nissl-stained sections, adult MR–/– mice, but not GRNesCre mice, show a significant reduction of granule cells in the hippocampus, most pronounced in the upper blade of the dentate gyrus (arrowheads). In the hilus of the dentate gyrus (asterisk), an increase in the number of neurons is seen in MR–/– mice. In the same areas of dentate gyrus in MR–/– mice where the granule cell number is reduced, an increase of activated astrocytes is found by immunostaining for activated MAP-kinase (MAPK). Increased cell density in the hilus is also demonstrated by immunostaining for calretinin, a marker for a subset of GABAergic hilus neurons.
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Fig. 2. Mossy fiber sprouting in the hippocampus of adult MR–/– mice. In comparison to wild-type mice with regular distribution of Timm-stained mossy fiber terminals, MR–/– mice demonstrate significantly prolonged intra/infrapyramidal projection fields (iip) that extend up to the distal end of CA3 (arrowheads). Quantitative morphometrical analysis confirmed that the intra/infrapyramidal projection field was on average twice as large in MR–/– mice, whereas the suprapyramidal and hilar projection fields were not significantly enlarged.
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Fig. 3. Reduced neurogenesis in the hippocampus of adult MR–/– mice. Proliferating hippocampal granule cells were labelled with the monoclonal antibody Ki67 directed against the proliferation marker Mib-1. Three representatively selected hippocampal sections at the level of the dorsal hippocampus were analysed in six mutant and six wild-type animals. On average, adult MR–/– mice exhibit only 29 labelled nuclei in the three sections analysed, while MR wild-type littermate mice show 44 Ki67 positive nuclei (P = 0.025, Student’s t-test). In contrast to MR–/– mice, GRNesCre mice demonstrate unaltered numbers of Ki67 positive nuclei when compared with their respective control littermates (GRNesCre exhibit 39, GRNesCre wild-type littermates 42 Ki67 labelled nuclei, respectively).
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