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

Author

Listed:
  • Jeffrey M. Welch

    (Department of Neurobiology,)

  • Jing Lu

    (Department of Neurobiology,
    Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China)

  • 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,
    Center for Neuroscience and Cell Biology, University of Coimbra)

  • Jin-Dong Ding

    (Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA)

  • Catia Feliciano

    (Department of Neurobiology,
    Gulbenkian PhD Programme in Biomedicine, Gulbenkian Science Institute)

  • 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,
    Center for Translational Neuroscience, Duke University Medical Center, Durham, North Carolina 27710, USA)

  • William C. Wetsel

    (Cell Biology, Neurobiology, and Mouse Behavioral and Neuroendocrine Analysis Core Facility)

  • Guoping Feng

    (Department of Neurobiology,)

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.

Suggested Citation

  • 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 , 2007. "Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice," Nature, Nature, vol. 448(7156), pages 894-900, August.
    • Handle: RePEc:nat:nature:v:448:y:2007:i:7156:d:10.1038_nature06104
    DOI: 10.1038/nature06104
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    Cited by:

    1. In Bum Lee & Eugene Lee & Na-Eun Han & Marko Slavuj & Jeong Wook Hwang & Ahrim Lee & Taeyoung Sun & Yehwan Jeong & Ja-Hyun Baik & Jae-Yong Park & Se-Young Choi & Jeehyun Kwag & Bong-June Yoon, 2024. "Persistent enhancement of basolateral amygdala-dorsomedial striatum synapses causes compulsive-like behaviors in mice," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Lukas M. von Ziegler & Amalia Floriou-Servou & Rebecca Waag & Rebecca R. Gupta & Oliver Sturman & Katharina Gapp & Christina A. Maat & Tobias Kockmann & Han-Yu Lin & Sian N. Duss & Mattia Privitera & , 2022. "Multiomic profiling of the acute stress response in the mouse hippocampus," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    3. Gwynne L. Davis & Adelaide R. Minerva & Argentina Lario & Linda D. Simmler & Carolyn I. Rodriguez & Lisa A. Gunaydin, 2021. "Ketamine increases activity of a fronto-striatal projection that regulates compulsive behavior in SAPAP3 knockout mice," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    4. Sean C. Piantadosi & Elizabeth E. Manning & Brittany L. Chamberlain & James Hyde & Zoe LaPalombara & Nicholas M. Bannon & Jamie L. Pierson & Vijay M. K Namboodiri & Susanne E. Ahmari, 2024. "Hyperactivity of indirect pathway-projecting spiny projection neurons promotes compulsive behavior," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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