title: GSK3β inhibition promotes synaptogenesis in Drosophila and mammalian neurons.
abstract: The PI3K-dependent activation of AKT results in the inhibition of GSK3β in most signaling pathways. These kinases regulate multiple neuronal processes including the control of synapse number as shown for Drosophila and rodents. Alzheimer disease's patients exhibit high levels of circulating GSK3β and, consequently, pharmacological strategies based on GSK3β antagonists have been designed. The approach, however, has yielded inconclusive results so far. Here, we carried out a comparative study in Drosophila and rats addressing the role of GSK3β in synaptogenesis. In flies, the genetic inhibition of the shaggy-encoded GSK3β increases the number of synapses, while its upregulation leads to synapse loss. Likewise, in three weeks cultured rat hippocampal neurons, the pharmacological inhibition of GSK3β increases synapse density and Synapsin expression. However, experiments on younger cultures (12 days) yielded an opposite effect, a reduction of synapse density. This unexpected finding seems to unveil an age- and dosage-dependent differential response of mammalian neurons to the stimulation/inhibition of GSK3β, a feature that must be considered in the context of human adult neurogenesis and pharmacological treatments for Alzheimer's disease based on GSK3β antagonists.
authors.affiliation: Structural Synaptic Plasticity Laboratory, Department of Neurodegenerative Diseases, Centro de Investigación Biomédica de La Rioja, Logroño, La Rioja, Spain.
authors.forename: Germán
authors.initials: G
authors.lastname: Cuesto
authors.affiliation: Department of Cellular, Molecular and Developmental Neurobiology, Cajal Institute, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: Sheila
authors.initials: S
authors.lastname: Jordán-Álvarez
authors.affiliation: Structural Synaptic Plasticity Laboratory, Department of Neurodegenerative Diseases, Centro de Investigación Biomédica de La Rioja, Logroño, La Rioja, Spain.
authors.forename: Lilian
authors.initials: L
authors.lastname: Enriquez-Barreto
authors.affiliation: Department of Cellular, Molecular and Developmental Neurobiology, Cajal Institute, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ferrús
authors.affiliation: Structural Synaptic Plasticity Laboratory, Department of Neurodegenerative Diseases, Centro de Investigación Biomédica de La Rioja, Logroño, La Rioja, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Morales
authors.affiliation: Department of Cellular, Molecular and Developmental Neurobiology, Cajal Institute, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Acebes
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology* / Q000201:enzymology; D006801:Humans; D009474:Neurons / Q000201:enzymology* / Q000502:physiology; D051381:Rats; D015398:Signal Transduction; D013569:Synapses / Q000201:enzymology* / Q000502:physiology; D016704:Synapsins / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D029721:Drosophila Proteins; D016704:Synapsins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; C080335:Sgg protein, Drosophila; D038362:Glycogen Synthase Kinase 3