Abstract
In restricted areas of the adult brain, like the subgranular zone of the dentate gyrus (DG), there is continuous production of new neurons. This process, named adult neurogenesis, is involved in important cognitive functions such as memory and learning. It requires the presence of newborn neurons that arise from neuronal stem cells, which divide and differentiate through successive stages in adulthood. In this work, we demonstrate that overexpression of glycogen synthase kinase (GSK) 3β in neural precursor cells (NPCs) using the glial fibrillary acidic protein promoter during DG development produces an increase in the neurogenic process, increasing NPCs numbers. Moreover, the transgenic mice show higher DG volume and increased number of mature granule neurons. In an attempt to compensate for these alterations, glial fibrillary acidic protein/GSK3β-overexpressing mice show increased levels of Dkk1 and sFRP3, two inhibitors of the Wnt-frizzled complex. We have also found behavioral differences between wild type and transgenic mice, indicating a higher rating in memory tasks for GSK3β-overexpressing mice compared with wild type mice. These data indicate that GSK3β is a crucial kinase in NPC physiology and suggest that this molecule plays a key role in the correct development of DG and adult neurogenesis in this region.
Highlights
Adult neurogenesis is the production of new neurons during development but throughout life
Mouse Design to Overexpress GSK3 in Neural Precursors— To analyze the role of GSK3 in neural precursor cells (NPCs), we have generated transgenic mice where GSK3 overexpression is driven by a glial fibrillary acidic protein (GFAP) promoter (GFAP/GSK3 mice; Fig. 1A)
These transgenic mice carry a bidirectional TetO promoter (Bi-TetO) followed by GSK3 cDNA encoding in 5Ј a myc epitope in one direction and a -galactosidase (-Gal) reporter gene fused with a nuclear location signal in the other (Fig. 1B)
Summary
Mice were bred at the Centro de Biología Molecular “Severo Ochoa” animal facility, under standard laboratory conditions in accordance with European Community Guidelines and handled in accordance with European and local animal care protocols. The mice were housed 4 –5/cage with food and water available ad libitum and maintained in a temperature-controlled environment on a 12/12-h light/dark cycle with light onset at 8 a.m. The studies in adult neurogenesis were done with GFAP/ GSK3 double transgenic, with all experimental procedures authorized by the Bioethics Committee of Centro de Biologıa Molecular Severo Ochoa (Universidad Autonoma de MadridConsejo Superior de Investigaciones Cientıficas, UAM-CSIC, Madrid, Spain). WT animals resulting from crossing GFAP-tTa line with C57/BL6 mice were used as a control group. All experiments were conducted in animals 3.5 months old, except those shown in Fig. 7 and Table 1
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