Estudio de la neurogénesis adulta en un modelo murino de sobreexpresión de la glucógeno sintasa quinasa-3 Beta en precursores neuronales

Abstract

Tesis doctoral inédita. Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 17-01-2014GSK3 plays an important role in many physiological processes such as microtubule dynamics, cell cycle division, glucose metabolism, apoptosis, embryonic development, cell differentiation and adult neurogenesis. We have previously reported the effects on dentate gyrus (DG) neurogenesis of overexpress GSK3β in adult neurons under CamKIIα promoter. These mice present atrophied DG and less neurogenic niches which show a reduced proliferative activity leading to almost a total depletion with age. Here, by using GFAP promoter, we have generated a transgenic mice overexpressing GSK3β in glial cells. First, differences have been detected in GFAP/OE GSK-3β mice due to GSK3β overexpression such as an increase in brain weight, volume of dentate gyrus and number of mature granule neurons. Interestingly, main astrocytes overexpressing GSK3β are those present in the cerebellum as well as those present in the SGZ of the hippocampus. Behavioral tests suggest that GSK3β overexpression can be helpful as demonstrated by the Rotarod test or by the increasing freezing time observed in the fear conditioning test. Focusing our study in the SGZ, we have demonstrated that the increase in DG observed in this animal model could be due in part to alterations in neurogenesis. Thus, we have detected an increase in the number of neural progenitor cells in the overexpressing mice by using molecular markers such as BLBP, Sox2 and DCX. In good agreement, neural precursors isolated from GFAP/OE GSK3 mice, exhibit increased cell proliferation in culture. However, although that animal model has a higher number of neuronal progenitors we did not observed differences in parameters such as cell proliferation, survival of newly generated neurons or division cycle reentry. Interestingly, an increase in Dkk1 y sFRP3 mRNA, inhibitors of Wnt-frizzled complex, is observed. Moreover, some alterations occur because an increase in active microglial cells as well as changes in levels of some cytokine molecules is observed. This could be the explanation for changes in morphology of dendritic tree observed in mature newborn neurons of GFAP/OE GSK3 after switching off the transgene. In summary, these findings suggest that an increase in GSK3β activity in neural progenitors provokes an increase in these precursors at least in SGZ as well an increase in granular neurons in the DG