title: Dual effects of increased glycogen synthase kinase-3β activity on adult neurogenesis.
abstract: Adult neurogenesis, the generation of new neurons during the adulthood, is a process controlled by several kinases and phosphatases among which GSK3β exerts important functions. This protein is particularly abundant in the central nervous system, and its activity deregulation is believed to play a key role in chronic disorders such as Alzheimer's disease. Previously, we reported that in vivo overexpression of GSK3β (Tet/GSK3β mice) causes alterations in adult neurogenesis, leading to a depletion of the neurogenic niches. Here, we have further characterized those alterations, finding a delay in the switching-off of doublecortin marker as well as changes in the survival and death rates of immature precursors and a decrease in the total number of mature neurons. Besides, we have highlighted the importance of the inflammatory environment, identifying eotaxin as a possible modulator of the detrimental effects on adult neurogenesis. Taking advantage of the conditional system, we have also explored whether these negative consequences of increasing GSK3 activity are susceptible to revert after doxycycline treatment. We show that transgene shutdown in symptomatic mice reverts microgliosis, abnormal eotaxin levels as well as the aforementioned alterations concerning immature neurons. Unexpectedly, the decrease in the number of mature neurons and neuronal precursor cells of the subgranular zone of Tet/GSK3β mice could not be reverted. Thus, alterations in adult neurogenesis and likely in neurodegenerative disorders can be restored in part, although neurogenic niche depletion represents a non-reversible damage persisting during lifetime with a remarkable impact in adult mature neurons.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas/UniversidadAutónoma de Madrid, Madrid, Spain.
authors.forename: Almudena
authors.initials: A
authors.lastname: Fuster-Matanzo
authors.forename: María
authors.initials: M
authors.lastname: Llorens-Martín
authors.forename: María Salomé
authors.initials: MS
authors.lastname: Sirerol-Piquer
authors.forename: José Manuel
authors.initials: JM
authors.lastname: García-Verdugo
authors.forename: Jesús
authors.initials: J
authors.lastname: Avila
authors.forename: Félix
authors.initials: F
authors.lastname: Hernández
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002470:Cell Survival; D054413:Chemokine CCL11 / Q000378:metabolism; D004268:DNA-Binding Proteins; D018891:Dentate Gyrus / Q000166:cytology / Q000201:enzymology; D000089622:Doublecortin Domain Proteins; D004790:Enzyme Induction; D017930:Genes, Reporter; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007381:Intermediate Filament Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D058953:Neural Stem Cells / Q000502:physiology; D055495:Neurogenesis; D009474:Neurons / Q000201:enzymology; D009479:Neuropeptides / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D055153:Stem Cell Niche; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
chemical_list: D015415:Biomarkers; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D004268:DNA-Binding Proteins; D000089622:Doublecortin Domain Proteins; D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; C492380:NeuN protein, mouse; D009479:Neuropeptides; D009687:Nuclear Proteins; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D001616:beta-Galactosidase