title: Palmitoylation of cdc42 Promotes Spine Stabilization and Rescues Spine Density Deficit in a Mouse Model of 22q11.2 Deletion Syndrome.
abstract: 22q11.2 deletion syndrome (22q11DS) is associated with learning and cognitive dysfunctions and a high risk of developing schizophrenia. It has become increasingly clear that dendritic spine plasticity is tightly linked to cognition. Thus, understanding how genes involved in cognitive disorders affect synaptic networks is a major challenge of modern biology. Several studies have pointed to a spine density deficit in 22q11DS transgenic mice models. Using the LgDel mouse model, we first quantified spine deficit at different stages using electron microscopy. Next we performed repetitive confocal imaging over several days on hippocampal organotypic cultures of LgDel mice. We show no imbalanced ratio between daily spine formation and spine elimination, but a decreased spine life expectancy. We corrected this impaired spine stabilization process by overexpressing ZDHHC8 palmitoyltransferase, whose gene belongs to the LgDel microdeletion. Overexpression of one of its substrates, the cdc42 brain-specific variant, under a constitutively active form (cdc42-palm-CA) led to the same result. Finally, we could rescue spine density in vivo, in adult LgDel mice, by injecting pups with a vector expressing cdc42-palm-CA. This study reveals a new role of ZDHHC8-cdc42-palm molecular pathway in postsynaptic structural plasticity and provides new evidence in favor of the dysconnectivity hypothesis for schizophrenia.
authors.affiliation: Department of Basic Neurosciences, Medical School, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Moutin
authors.affiliation: Department of Basic Neurosciences, Medical School, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: I
authors.initials: I
authors.lastname: Nikonenko
authors.affiliation: Department of Basic Neurosciences, Medical School, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Stefanelli
authors.affiliation: Cellular Neurophysiology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Wirth
authors.affiliation: Cellular Neurophysiology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Ponimaskin
authors.affiliation: Department of Basic Neurosciences, Medical School, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: De Roo
authors.affiliation: Department of Basic Neurosciences, Medical School, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Muller
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D049229:Dendritic Spines / Q000378:metabolism* / Q000648:ultrastructure; D004062:DiGeorge Syndrome / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D066298:In Vitro Techniques; D054878:Lipoylation / Q000187:drug effects / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D051379:Mice; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008953:Models, Anatomic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009924:Organ Culture Techniques; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C512641:Palm protein, mouse; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D000217:Acyltransferases; C534673:ZDHHC8 protein, mouse; C097702:synaptojanin; D010744:Phosphoric Monoester Hydrolases; D020764:cdc42 GTP-Binding Protein
keywords: DiGeorge syndrome; confocal imaging; dendritic spine; hippocampus; plasticity