title: Loss of neuronal GSK3β reduces dendritic spine stability and attenuates excitatory synaptic transmission via β-catenin.
abstract: Central nervous glycogen synthase kinase 3β (GSK3β) is implicated in a number of neuropsychiatric diseases, such as bipolar disorder, depression, schizophrenia, fragile X syndrome or anxiety disorder. Many drugs employed to treat these conditions inhibit GSK3β either directly or indirectly. We studied how conditional knockout of GSK3β affected structural synaptic plasticity. Deletion of the GSK3β gene in a subset of cortical and hippocampal neurons in adult mice led to reduced spine density. In vivo imaging revealed that this was caused by a loss of persistent spines, whereas stabilization of newly formed spines was reduced. In electrophysiological recordings, these structural alterations correlated with a considerable drop in the frequency and amplitude of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-dependent miniature excitatory postsynaptic currents. Expression of constitutively active β-catenin caused reduction in spine density and electrophysiological alterations similar to GSK3β knockout, suggesting that the effects of GSK3β knockout were mediated by the accumulation of β-catenin. In summary, changes of dendritic spines, both in quantity and in morphology, are correlates of experience-dependent synaptic plasticity; thus, these results may help explain the mechanism of action of psychotropic drugs inhibiting GSK3β.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig Maximilian University Munich, Munich, Germany.
authors.forename: S M
authors.initials: SM
authors.lastname: Ochs
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig Maximilian University, Munich, Germany.
authors.forename: M M
authors.identifier: 0000000180374907
authors.initials: MM
authors.lastname: Dorostkar
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig Maximilian University Munich, Munich, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Aramuni
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig Maximilian University, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schön
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig Maximilian University Munich, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Filser
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig Maximilian University, Munich, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Pöschl
authors.affiliation: Experimental Genetics Group-LEGTEGG, Department of Human Genetics KU Leuven, Leuven, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Kremer
authors.affiliation: Experimental Genetics Group-LEGTEGG, Department of Human Genetics KU Leuven, Leuven, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Van Leuven
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig Maximilian University Munich, Munich, Germany.
authors.forename: S V
authors.initials: SV
authors.lastname: Ovsepian
authors.affiliation: 1] German Center for Neurodegenerative Diseases (DZNE), Ludwig Maximilian University Munich, Munich, Germany [2] Center for Neuropathology and Prion Research, Ludwig Maximilian University, Munich, Germany [3] Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Herms
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D049229:Dendritic Spines / Q000502:physiology*; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics*; D018756:GABA Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D038362:Glycogen Synthase Kinase 3 / Q000172:deficiency* / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D001426:Bacterial Proteins; D018683:Excitatory Amino Acid Agents; D018756:GABA Antagonists; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D008164:Luminescent Proteins; D010852:Picrotoxin; D013629:Tamoxifen; D051176:beta Catenin; C054562:yellow fluorescent protein, Bacteria; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse