Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice

Jeffrey M. Welch, Jing Lu, Ramona M. Rodriguiz, Nicholas C. Trotta, Joao Peca, Jin-Dong Ding, Catia Feliciano, Meng Chen, J. Paige Adams, Jianhong Luo, Serena M. Dudek, Richard J. Weinberg, Nicole Calakos, William C. Wetsel and Guoping Feng ()
Additional contact information
Jeffrey M. Welch: Department of Neurobiology,
Jing Lu: Department of Neurobiology,
Ramona M. Rodriguiz: Cell Biology, Neurobiology, and Mouse Behavioral and Neuroendocrine Analysis Core Facility
Nicholas C. Trotta: Department of Neurobiology,
Joao Peca: Department of Neurobiology,
Jin-Dong Ding: Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA
Catia Feliciano: Department of Neurobiology,
Meng Chen: Center for Translational Neuroscience, Duke University Medical Center, Durham, North Carolina 27710, USA
J. Paige Adams: National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA
Jianhong Luo: Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
Serena M. Dudek: National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA
Richard J. Weinberg: Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA
Nicole Calakos: Department of Neurobiology,
William C. Wetsel: Cell Biology, Neurobiology, and Mouse Behavioral and Neuroendocrine Analysis Core Facility
Guoping Feng: Department of Neurobiology,

Nature, 2007, vol. 448, issue 7156, 894-900

Abstract: 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.

Date: 2007
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DOI: 10.1038/nature06104

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