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

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Welch, JM; Lu, J; Rodriguiz, RM; Trotta, NC; Peca, J; Ding, J-D; Feliciano, C; Chen, M; Adams, JP; Luo, J; Dudek, SM; Weinberg, RJ; Calakos, N; Wetsel, WC; Feng, G

Published Date

  • August 23, 2007

Published In

Volume / Issue

  • 448 / 7156

Start / End Page

  • 894 - 900

PubMed ID

  • 17713528

Electronic International Standard Serial Number (EISSN)

  • 1476-4687

Digital Object Identifier (DOI)

  • 10.1038/nature06104

Language

  • eng

Conference Location

  • England