title: Inhibition of GSK3β rescues hippocampal development and learning in a mouse model of CDKL5 disorder.
abstract: Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in a rare neurodevelopmental disorder characterized by early-onset seizures, severe developmental delay, intellectual disability and Rett syndrome-like features. CDKL5 is highly expressed in the brain during early postnatal stages, suggesting its importance for brain maturation. Using a newly-generated Cdkl5 knockout (Cdkl5 -/Y) mouse, we recently found that loss of Cdkl5 impairs postnatal hippocampal development with a reduction in neuronal precursor survival and maturation. These defects were accompanied by increased activity of the glycogen synthase kinase 3β (GSK3β) a crucial inhibitory regulator of many neurodevelopmental processes. The goal of the current study was to establish whether inhibition of GSK3β corrects hippocampal developmental defects due to Cdkl5 loss. We found that treatment with the GSK3β inhibitor SB216763 restored neuronal precursor survival, dendritic maturation, connectivity and hippocampus-dependent learning and memory in the Cdkl5 -/Y mouse. Importantly, these effects were retained one month after treatment cessation. At present, there are no therapeutic strategies to improve the neurological defects of subjects with CDKL5 disorder. Current results point at GSK3β inhibitors as potential therapeutic tools for the improvement of abnormal brain development in CDKL5 disorder.
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fuchs
authors.affiliation: Department of Medical and Clinical Sciences, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Rimondini
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy.
authors.forename: Rocchina
authors.initials: R
authors.lastname: Viggiano
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Trazzi
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: De Franceschi
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy.
authors.forename: Renata
authors.initials: R
authors.lastname: Bartesaghi
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy. Electronic address: eelisabetta.ciani@unibo.it.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ciani
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development / Q000473:pathology; D007211:Indoles / Q000494:pharmacology*; D007859:Learning Disabilities / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008301:Maleimides / Q000494:pharmacology*; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D065852:Spatial Memory
chemical_list: D007211:Indoles; D008301:Maleimides; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D047428:Protein Kinase Inhibitors; C417521:SB 216763; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D017346:Protein Serine-Threonine Kinases; C533690:CDKL5 protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: CDKL5 disorder; Encephalopathy; GSK3β inhibitor; Pharmacotherapy; Rescue of hippocampal developmental