Abstract
Adult hippocampal neurogenesis (AHN) is crucial for the maintenance of hippocampal function. Several neurodegenerative diseases such as Alzheimer’s disease (AD) are accompanied by memory deficits that could be related to alterations in AHN. Here, we took advantage of a conditional mouse model to study the involvement of glycogen synthase kinase-3β (GSK-3β) overexpression (OE) in AHN. By injecting GFP- and PSD95-GFP-expressing retroviruses, we have determined that hippocampal GSK-3β-OE causes dramatic alterations in both dendritic tree morphology and post-synaptic densities in newborn neurons. Alterations in previously damaged neurons were reverted by switching off the transgenic system and also by using a physiological approach (environmental enrichment) to increase hippocampal plasticity. Furthermore, comparative morphometric analysis of granule neurons from patients with AD and from GSK-3β overexpressing mice revealed shared morphological alterations. Taken together, these data indicate that GSK-3β is crucial for hippocampal function, thereby supporting this kinase as a relevant target for the treatment of AD.
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Acknowledgements
This study was funded by grants from Spanish Ministry of Health (SAF 2006-02424, BFU-2008-03980 and BFU-2010-21507), the Comunidad de Madrid (SAL/0202/2006), the Fundación M. Botín, the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), and an institutional grant from the Fundación R Areces. Human control samples were generously provided by the Biobanco del Hospital Universitario Reina Sofia (Córdoba, Spain), and we thank Dr R Sánchez Sánchez for providing samples. AD samples were generously provided by the Banco de Tejidos de la Fundación CIEN (Madrid, Spain). We thank Drs I Fernaud-Espinosa and A Kastanauskaite for the estimating the volume of PSD95-GFP+ clusters; Dr V Borrell for kindly providing GFP-expressing retroviruses; Prof F.H. Gage for generously providing the plasmids used for the production of GFP-expressing retroviruses and Prof C Lois for kindly providing the plasmids used for the production of PSD95-GFP viruses. The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this manuscript. Authors would like to thank Elena Langa for her help with animal experiments and Nuria de la Torre for her help with writing the manuscript.
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Llorens-Martín, M., Fuster-Matanzo, A., Teixeira, C. et al. GSK-3β overexpression causes reversible alterations on postsynaptic densities and dendritic morphology of hippocampal granule neurons in vivo. Mol Psychiatry 18, 451–460 (2013). https://doi.org/10.1038/mp.2013.4
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DOI: https://doi.org/10.1038/mp.2013.4
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