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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Acknowledgements
We thank J. Gross, K. Phend and L. Qiu for technical assistance, and L. Phillips, L. Nguyen, S. Greeter, J. Wilkins and M. Fukui for assistance in behavioural testing and decoding of video tapes. We thank M. Ehlers for the anti-NR2B antibody and E. Kim for the anti-Shank antibody. We also thank M. Caron, M. Ehlers, Z. He, J. Sanes, F. Wang, A. West and members of the Feng laboratory for critical reading of the manuscript. This work was supported by grants from NINDS and NIMH to G.F., R.J.W. and N.C.; by unrestricted funds to W.C.W.; and by the Intramural Research Program of NIEHS to S.M.D. J.M.W. was supported by an NSF pre-doctoral fellowship and an NIH National Research Service Award. N.C. is a recipient of a Klingenstein Fellowship in the Neurosciences and a NARSAD Young Investigator Award. G.F. is a recipient of a Sloan Fellowship, a Klingenstein Fellowship in the Neurosciences, an EJLB Foundation Scholar Research Program Award, a McKnight Neuroscience of Brain Disorders Award and a Hartwell Foundation Individual Biomedical Research Award.
Author Contributions J.M.W., J. Lu, R.M.R., N.C.T., J.P., J.-D.D., C.F., M.C. and J.P.A. participated in the design, analysis and execution of experiments. G.F., N.C., W.C.W., J.M.W., R.J.W., S.M.D. and J. Luo participated in the design, analysis and interpretation of experiments.
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Welch, J., Lu, J., Rodriguiz, R. et al. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 448, 894–900 (2007). https://doi.org/10.1038/nature06104
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