Article
Nature 448, 894-900 (23 August 2007) | doi:10.1038/nature06104; Received 30 May 2007; Accepted 16 July 2007
Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice
Jeffrey M. Welch1,9, Jing Lu1,4,9, Ramona M. Rodriguiz2, Nicholas C. Trotta1, Joao Peca1,5, Jin-Dong Ding6, Catia Feliciano1,7, Meng Chen3, J. Paige Adams8, Jianhong Luo4, Serena M. Dudek8, Richard J. Weinberg6, Nicole Calakos1,3, William C. Wetsel2 & Guoping Feng1
- Department of Neurobiology,
- Departments of Psychiatry and Behavioral Sciences, Cell Biology, Neurobiology, and Mouse Behavioral and Neuroendocrine Analysis Core Facility,
- Division of Neurology, Center for Translational Neuroscience, Duke University Medical Center, Durham, North Carolina 27710, USA
- Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal
- Department of Cell and Developmental Biology, Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA
- Gulbenkian PhD Programme in Biomedicine, Gulbenkian Science Institute, 2781-901 Oeiras, Portugal
- National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA
- These authors contributed equally to this work.
Correspondence to: Guoping Feng1 Correspondence and requests for materials should be addressed to G.F. (Email: feng@neuro.duke.edu).
Abstract
Obsessive-compulsive disorder (OCD) is an anxiety-spectrum disorder characterized by persistent intrusive thoughts (obsessions) and repetitive actions (compulsions). Dysfunction of cortico-striato-thalamo-cortical circuitry is implicated in OCD, although the underlying pathogenic mechanisms are unknown. SAP90/PSD95-associated protein 3 (SAPAP3; also known as DLGAP3) is a postsynaptic scaffolding protein at excitatory synapses that is highly expressed in the striatum. Here we show that mice with genetic deletion of Sapap3 exhibit increased anxiety and compulsive grooming behaviour leading to facial hair loss and skin lesions; both behaviours are alleviated by a selective serotonin reuptake inhibitor. Electrophysiological, structural and biochemical studies of Sapap3-mutant mice reveal defects in cortico-striatal synapses. Furthermore, lentiviral-mediated selective expression of Sapap3 in the striatum rescues the synaptic and behavioural defects of Sapap3-mutant mice. These findings demonstrate a critical role for SAPAP3 at cortico-striatal synapses and emphasize the importance of cortico-striatal circuitry in OCD-like behaviours.
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