title: GSK-3β and MMP-9 Cooperate in the Control of Dendritic Spine Morphology.
abstract: Changes in the morphology of dendritic spines are prominent during learning and in different neurological and neuropsychiatric diseases, including those in which glycogen synthase kinase-3β (GSK-3β) has been implicated. Despite much evidence of the involvement of GSK-3β in functional synaptic plasticity, it is unclear how GSK-3β controls structural synaptic plasticity (i.e., the number and shape of dendritic spines). In the present study, we used two mouse models overexpressing and lacking GSK-3β in neurons to investigate how GSK-3β affects the structural plasticity of dendritic spines. Following visualization of dendritic spines with DiI dye, we found that increasing GSK-3β activity increased the number of thin spines, whereas lacking GSK-3β increased the number of stubby spines in the dentate gyrus. Under conditions of neuronal excitation, increasing GSK-3β activity caused higher activity of extracellularly acting matrix metalloproteinase-9 (MMP-9), and MMP inhibition normalized thin spines in GSK-3β overexpressing mice. Administration of the nonspecific GSK-3β inhibitor lithium in animals with active MMP-9 and animals lacking MMP-9 revealed that GSK-3β and MMP-9 act in concert to control dendritic spine morphology. Altogether, our data demonstrate that the dysregulation of GSK-3β activity has dramatic consequences on dendritic spine morphology, implicating MMP-9 as a mediator of GSK-3β-induced synaptic alterations.
authors.affiliation: Laboratory of Neurobiology, The Nencki Institute of Experimental Biology, 3 Pasteur, 02-093, Warsaw, Poland.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kondratiuk
authors.affiliation: Laboratory of Neuroinformatics, The Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Szymon
authors.initials: S
authors.lastname: Łęski
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, The International Institute of Molecular and Cell Biology, Warsaw, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Urbańska
authors.affiliation: Faculty of Mathematics, Informatics, and Mechanics, University of Warsaw, Warsaw, Poland.
authors.forename: Przemysław
authors.initials: P
authors.lastname: Biecek
authors.affiliation: Department of Human Genetics, Experimental Genetics Group - LEGTEGG, KULeuven, Leuven, Belgium.
authors.forename: Herman
authors.initials: H
authors.lastname: Devijver
authors.affiliation: Department of Human Genetics, Experimental Genetics Group - LEGTEGG, KULeuven, Leuven, Belgium.
authors.forename: Benoit
authors.initials: B
authors.lastname: Lechat
authors.affiliation: Department of Human Genetics, Experimental Genetics Group - LEGTEGG, KULeuven, Leuven, Belgium.
authors.forename: Fred
authors.initials: F
authors.lastname: Van Leuven
authors.affiliation: Laboratory of Neurobiology, The Nencki Institute of Experimental Biology, 3 Pasteur, 02-093, Warsaw, Poland. l.kaczmarek@nencki.gov.pl.
authors.forename: Leszek
authors.initials: L
authors.lastname: Kaczmarek
authors.affiliation: Laboratory of Neurobiology, The Nencki Institute of Experimental Biology, 3 Pasteur, 02-093, Warsaw, Poland. t.jaworski@nencki.gov.pl.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Jaworski
mesh_terms: D000818:Animals; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar
chemical_list: D047428:Protein Kinase Inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Dendritic spines; GSK-3β; Imaging; MMP-9; Synaptic plasticity; Transgenic mice