title: Dishevelled-2 regulates cocaine-induced structural plasticity and Rac1 activity in the nucleus accumbens.
abstract: Chronic cocaine exposure increases the density of dendritic spines on medium spiny neurons (MSNs), the predominant neuronal cell type of the nucleus accumbens (NAc), a key brain reward region. We recently showed that suppression of Rac1, a small GTPase, is a critical mediator of this structural plasticity, but the upstream determinants of Rac1 activity in this context remain to be elucidated. In this study we examined whether isoforms of Dishevelled, a key hub protein of multiple branches of Wnt signaling, including Rac1, are regulated in the NAc by chronic cocaine, and whether these Dishevelled isoforms control Rac1 activity in this brain region in vivo. We found that chronic cocaine administration decreased expression of Dishevelled-2, and several other Wnt signaling components, in the NAc, and that overexpression of Dishevelled-2, but not Dishevelled-1, conversely upregulated Rac1 activity and prevented the cocaine induction of dendritic spines on NAc MSNs. We posit that the cocaine-induced downregulation of Dishevelled-2 in the NAc is an upstream regulator of Rac1 activity and plays an important role in the dynamic structural plasticity of NAc MSNs seen in response to chronic cocaine exposure.
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dias
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY, USA.
authors.forename: David
authors.initials: D
authors.lastname: Dietz
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Mazei-Robison
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY, USA.
authors.forename: Haosheng
authors.initials: H
authors.lastname: Sun
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Damez-Werno
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY, USA.
authors.forename: Deveroux
authors.initials: D
authors.lastname: Ferguson
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wilkinson
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Magida
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Gao
authors.affiliation: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Neve
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY, USA. Electronic address: eric.nestler@mssm.edu.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism / Q000473:pathology; D049229:Dendritic Spines / Q000187:drug effects* / Q000648:ultrastructure; D000072261:Dishevelled Proteins; D008297:Male; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; C000606579:Dvl1 protein, mouse; C000606582:Dvl2 protein, mouse; D010750:Phosphoproteins; D020830:rac1 GTP-Binding Protein; D003042:Cocaine
keywords: Dendritic spines; Medium spiny neurons; Morphological plasticity; Wnt signaling