Palmitoylation of cdc42 Promotes Spine Stabilization and Rescues Spine Density Deficit in a Mouse Model of 22q11.2 Deletion Syndrome

• Published in: Cerebral cortex (New York, N.Y. 1991) Vol. 27; no. 7; pp. 3618 - 3629
• Main Authors: Moutin, E, Nikonenko, I, Stefanelli, T, Wirth, A, Ponimaskin, E, De Roo, M, Muller, D
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press (OUP) 01-07-2017
• Subjects: Acyltransferases - genetics; Acyltransferases - metabolism; Acyltransferases - therapeutic use; Age Factors; Animals; Animals, Newborn; cdc42 GTP-Binding Protein - genetics; cdc42 GTP-Binding Protein - metabolism; Dendritic Spines - metabolism; Dendritic Spines - ultrastructure; DiGeorge Syndrome - genetics; DiGeorge Syndrome - pathology; DiGeorge Syndrome - therapy; Disease Models, Animal; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Hippocampus - cytology; Humans; In Vitro Techniques; Life Sciences; Lipoylation - drug effects; Lipoylation - genetics; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membrane Proteins - therapeutic use; Mice; Microscopy, Confocal; Microscopy, Electron; Models, Anatomic; Mutation - genetics; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Organ Culture Techniques; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Transduction, Genetic; confocal imaging; plasticity; dendritic spine; DiGeorge syndrome; hippocampus
• ISSN: 1047-3211; 1460-2199
• DOI: 10.1093/cercor/bhw183

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.