Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6 - PubMed (original) (raw)

Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6

Luc Vallières et al. J Neurosci. 2002.

Abstract

Postnatal neurogenesis can be modulated after brain injury, but the role of the attendant expression of inflammatory mediators in such responses remains to be determined. Here we report that transgenically directed production of interleukin-6 (IL-6) by astroglia decreased overall neurogenesis by 63% in the hippocampal dentate gyrus of young adult transgenic mice. The proliferation, survival, and differentiation of neural progenitor cells labeled with the thymidine analog bromodeoxyuridine were all reduced in the granule cell layer of these mice, whereas their distribution and gliogenesis appeared normal. These effects were not a consequence of general toxicity of the IL-6 transgene, because they were manifested in the absence of neuronal death and of major changes in glial cell number and morphology. These findings suggest that long-term exposure of the brain to proinflammatory mediators such as IL-6, as is seen in certain degenerative disorders and infections, can interfere with adult neurogenesis.

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Figures

Fig. 1.

Fig. 1.

IL-6 transgene expression in the hippocampus revealed by β-gal immunohistochemistry. Brightfield photomicrographs of neutral red counterstained material show a lack of β-gal staining in the hippocampus of a wild-type mouse (A); β-gal staining in the hippocampus of an IL-6 transgenic mouse (B); higher magnification of β-gal staining in the dentate gyrus, showing many positive cells at the border between the granule cell layer and the hilus (C); a radial-like astrocyte within the granule cell layer expressing the IL-6 transgene (D); protoplasmic astrocytes of the gray matter (E); and blood vessel-associated astrocytes (F). CA1–CA3, Fields CA1–CA3 of Ammon's horn; CC, cerebral cortex;DG, dentate gyrus; GCL, granule cell layer; LDT, lateral dorsal thalamic nucleus;ML, molecular layer. The _asterisk_indicates lumen of blood vessel.

Fig. 2.

Fig. 2.

Neuronal integrity and gliosis in the dentate gyrus revealed by Fluoro-jade, GFAP, and Iba-1 histochemistry. Confocal laser scanning microscopic images of sections through the dentate gyrus show absence of Fluoro-jade staining in a wild-type (WT) mouse (A), absence of Fluoro-jade staining in an IL-6 transgenic (TG) mouse (B), Fluoro-jade-positive cells in the hilar region of a control mouse subjected to seizures (C), GFAP immunoreactivity in a WT mouse (D), GFAP immunostaining indicative of a mild astrogliosis in a TG mouse (E), hypertrophic reactive astrocytes in the hilus of a control mouse after seizures (F), Iba-1 immunoreactivity in a WT mouse (G), Iba-1 immunostaining indicating a moderate microgliosis in a TG mouse (H), and rounded, hypertrophied microglia in the hilus of a control mouse after seizures (I). GCL, Granule cell layer.

Fig. 3.

Fig. 3.

Effect of long-term IL-6 transgene expression on progenitor cell proliferation (day 1) and survival (day 31) in the granule cell layer of the dentate gyrus. A, Mean ± SEM of BrdU-labeled cells in the granule cell layer. B, Mean ± SEM of BrdU-labeled cells in the hilar region.TG, Transgenic; WT, wild-type. *p = 0.05; **p < 0.01.

Fig. 4.

Fig. 4.

Progenitor cell distribution and phenotype in the dentate gyrus of wild-type and IL-6 transgenic mice. Differential interference contrast images show BrdU-positive cells in the dentate gyrus of wild-type (WT) mice (A) and IL-6 transgenic (TG) mice (B), both killed 1 d after the final BrdU injection. Merged confocal images show triple immunolabeling for BrdU (red), NeuN (green), and S100β (blue) in the granule cell layer of WT (C) and TG (E) mice killed 31 d after final BrdU injections. D, F, The same images as seen in C and E, respectively, but without BrdU labeling. GCL, Granule cell layer.Arrowheads indicate BrdU-positive cells double-labeled with NeuN. Arrows indicate BrdU-positive cells not labeled with NeuN.

Fig. 5.

Fig. 5.

Effect of long-term IL-6 transgene expression on progenitor differentiation in the granule cell layer 31 d after BrdU injection. Data are expressed as mean ± SEM of BrdU-labeled cells. TG, Transgenic; WT, wild-type. *p < 0.01.

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