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Retroviral induction of GSK-3β expression blocks the stimulatory action of physical exercise on the maturation of newborn neurons

Abstract

Adult hippocampal neurogenesis (AHN) is a key process for certain types of hippocampal-dependent learning. Alzheimer’s disease (AD) is accompanied by memory deficits related to alterations in AHN. Given that the increased activity of GSK-3β has been related to alterations in the population of hippocampal granule neurons in AD patients, we designed a novel methodology by which to induce selective GSK-3β overexpression exclusively in newborn granule neurons. To this end, we injected an rtTA-IRES-EGFP-expressing retrovirus into the hippocampus of tTO-GSK-3β mice. Using this novel retroviral strategy, we found that GSK-3β caused a cell-autonomous impairment of the morphological and synaptic maturation of newborn neurons. In addition, we examined whether GSK-3β overexpression in newborn neurons limits the effects of physical activity. While physical exercise increased the number of dendritic spines, the percentage of mushroom spines, and the head diameter of the same in tet-OFF cells, these effects were not triggered in tet-ON cells. This observation suggests that GSK-3β blocks the stimulatory actions of exercise. Given that the activity of GSK-3β is increased in the brains of individuals with AD, these data may be relevant for non-pharmacological therapies for AD.

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Acknowledgments

This study was funded by grants from the Spanish Ministry of Health (SAF-2014-5040-P), and the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII) (J. Ávila); the Japan Society for the promotion of Science (post-doctoral fellowship to M. Llorens-Martín); and the Alzheimers Association (2015-NIRG-340709) (M. Llorens-Martín). The authors thank E. García for help producing retroviral vectors and F. H. Gage for providing the plasmids used for the production of GFP-expressing retroviruses.

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Correspondence to María Llorens-Martín or Jesús Ávila.

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M. Llorens-Martín and C. M. Teixeira contributed equally to this work.

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18_2016_2181_MOESM1_ESM.tif

Supplementary Figure S1: Phenotype of cells infected by the retrovirus. A-B: In order to analyze the phenotype of the cells infected by the rtTA-IRES-EGFP retrovirus and to compare it with that of cells infected by a CAG-GFP-expressing retrovirus [2], we quantified the percentage of cells either GFP+ or EGFP+ that expressed the neuroblast marker Doublecortin (DCX) and GFAP at 1 week post-injection (A), and the mature neuronal marker NeuN and DCX at 4 weeks post-injection (B). The percentage of DCX+, GFAP+ and NeuN+ cells did not differ between cells infected by either the CAG-GFP-expressing or the rtTA-IRES-EGFP retroviruses. C: In order to study whether GSK-3β overexpression affected the generation of newborn neurons, the phenotype of EGFP+ cells was analyzed in both tet-OFF and tet-ON conditions 4 weeks after rtTA-IRES-EGFP retrovirus injection in the hippocampus of tTO-GSK-3β mice. Quantification of the percentage of EGFP+ cells that expressed NeuN+ and DCX revealed no significant differences between tet-OFF and tet-ON conditions. (TIFF 3407 kb)

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Llorens-Martín, M., Teixeira, C.M., Jurado-Arjona, J. et al. Retroviral induction of GSK-3β expression blocks the stimulatory action of physical exercise on the maturation of newborn neurons. Cell. Mol. Life Sci. 73, 3569–3582 (2016). https://doi.org/10.1007/s00018-016-2181-6

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Keywords

  • GSK-3β
  • Physical exercise
  • Adult neurogenesis
  • Hippocampus
  • Retrovirus
  • rtTA