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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Karno, M., Golding, J. M., Sorenson, S. B. & Burnam, M. A. The epidemiology of obsessive-compulsive disorder in five US communities. Arch. Gen. Psychiatry 45, 1094–1099 (1988)
Torres, A. R. et al. Obsessive-compulsive disorder: prevalence, comorbidity, impact, and help-seeking in the British national psychiatric morbidity survey of 2000. Am. J. Psychiatry 163, 1978–1985 (2006)
Swedo, S. E. & Snider, L. A. in Neurobiology of Mental Illness (eds Nestler, E. J & Charney, D.S.) 628–638 (Oxford Univ. Press, New York, 2004)
Graybiel, A. M. & Rauch, S. L. Toward a neurobiology of obsessive-compulsive disorder. Neuron 28, 343–347 (2000)
Aouizerate, B. et al. Pathophysiology of obsessive-compulsive disorder: a necessary link between phenomenology, neuropsychology, imagery and physiology. Prog. Neurobiol. 72, 195–221 (2004)
Hanna, G. L. et al. Genome-wide linkage analysis of families with obsessive-compulsive disorder ascertained through pediatric probands. Am. J. Med. Genet. 114, 541–552 (2002)
Shugart, Y. Y. et al. Genomewide linkage scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q. Mol. Psychiatry 11, 763–770 (2006)
Nestadt, G. et al. A family study of obsessive-compulsive disorder. Arch. Gen. Psychiatry 57, 358–363 (2000)
Inouye, E. Similar and dissimilar manifestations of obsessive-compulsive neurosis in monozygotic twins. Am. J. Psychiatry 121, 1171–1175 (1965)
Carey, G. & Gottesman, I. I. in Anxiety: New Research and Changing Concepts (eds Klein, D.F. & Rabkin J.) 117–136 (Raven Press, New York, 1981)
Chakrabarty, K., Bhattacharyya, S., Christopher, R. & Khanna, S. Glutamatergic dysfunction in OCD. Neuropsychopharmacology 30, 1735–1740 (2005)
Kim, E. et al. GKAP, a novel synaptic protein that interacts with the guanylate kinase-like domain of the PSD-95/SAP90 family of channel clustering molecules. J. Cell Biol. 136, 669–678 (1997)
Takeuchi, M. et al. SAPAPs. A family of PSD-95/SAP90-associated proteins localized at postsynaptic density. J. Biol. Chem. 272, 11943–11951 (1997)
Scannevin, R. H. & Huganir, R. L. Postsynaptic organization and regulation of excitatory synapses. Nature Rev. Neurosci. 1, 133–141 (2000)
Kim, E. & Sheng, M. PDZ domain proteins of synapses. Nature Rev. Neurosci. 5, 771–781 (2004)
Funke, L., Dakoji, S. & Bredt, D. S. Membrane-associated guanylate kinases regulate adhesion and plasticity at cell junctions. Annu. Rev. Biochem. 74, 219–245 (2005)
Welch, J. W., Wang, D. & Feng, G. Differential mRNA expression and protein localization of the SAP90/PSD-95-associated proteins (SAPAPs) in the nervous system of the mouse. J. Comp. Neurol. 472, 24–39 (2004)
Kindler, S., Rehbein, M., Classen, B., Richter, D. & Bockers, T. M. Distinct spatiotemporal expression of SAPAP transcripts in the developing rat brain: a novel dendritically localized mRNA. Brain Res. Mol. Brain Res. 126, 14–21 (2004)
Malinow, R. & Malenka, R. C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002)
Prybylowski, K. & Wenthold, R. J. N-Methyl-D-aspartate receptors: subunit assembly and trafficking to the synapse. J. Biol. Chem. 279, 9673–9676 (2004)
Nicoll, R. A., Tomita, S. & Bredt, D. S. Auxiliary subunits assist AMPA-type glutamate receptors. Science 311, 1253–1256 (2006)
Sheng, M., Cummings, J., Roldan, L. A., Jan, Y. N. & Jan, L. Y. Changing subunit composition of heteromeric NMDA receptors during development of rat cortex. Nature 368, 144–147 (1994)
Shi, J., Aamodt, S. M. & Constantine-Paton, M. Temporal correlations between functional and molecular changes in NMDA receptors and GABA neurotransmission in the superior colliculus. J. Neurosci. 17, 6264–6276 (1997)
Stocca, G. & Vicini, S. Increased contribution of NR2A subunit to synaptic NMDA receptors in developing rat cortical neurons. J. Physiol. 507, 13–24 (1998)
Tovar, K. R. & Westbrook, G. L. The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J. Neurosci. 19, 4180–4188 (1999)
Chapman, D. E., Keefe, K. A. & Wilcox, K. S. Evidence for functionally distinct synaptic NMDA receptors in ventromedial versus dorsolateral striatum. J. Neurophysiol. 89, 69–80 (2003)
Li, L., Murphy, T. H., Hayden, M. R. & Raymond, L. A. Enhanced striatal NR2B-containing methyl-D-aspartate receptor-mediated synaptic currents in a mouse model of Huntington disease. J. Neurophysiol. 92, 2738–2746 (2004)
Sans, N. et al. A developmental change in NMDA receptor-associated proteins at hippocampal synapses. J. Neurosci. 20, 1260–1271 (2000)
Barria, A. & Malinow, R. Subunit-specific NMDA receptor trafficking to synapses. Neuron 35, 345–353 (2002)
Prybylowski, K. et al. The synaptic localization of NR2B-containing NMDA receptors is controlled by interactions with PDZ proteins and AP-2. Neuron 47, 845–857 (2005)
van Zundert, B., Yoshii, A. & Constantine-Paton, M. Receptor compartmentalization and trafficking at glutamate synapses: a developmental proposal. Trends Neurosci. 27, 428–437 (2004)
Valtschanoff, J. G. & Weinberg, R. J. Laminar organization of the NMDA receptor complex within the postsynaptic density. J. Neurosci. 21, 1211–1217 (2001)
Day, M. et al. Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models. Nature Neurosci. 9, 251–259 (2006)
Kreitzer, A. C. & Malenka, R. C. Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models. Nature 445, 643–647 (2007)
Surmeier, D. J., Ding. J, Day, M., Wang, Z. & Shen, W. D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons. Trends Neurosci. 30, 228–235 (2007)
Arnold, P. D. et al. Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study. Psychopharmacology 174, 530–538 (2004)
Arnold, P. D., Sicard, T., Burroughs, E., Richter, M. A. & Kennedy, J. L. Glutamate transporter gene SLC1A1 associated with obsessive-compulsive disorder. Arch. Gen. Psychiatry 63, 769–776 (2006)
Dickel, D. E. et al. Association testing of the positional and functional candidate gene SLC1A1/EAAC1 in early-onset obsessive-compulsive disorder. Arch. Gen. Psychiatry 63, 778–785 (2006)
Feng, G. et al. Dual requirement for gephyrin in glycine receptor clustering and molybdoenzyme activity. Science 282, 1321–1324 (1998)
Greer, J. M. & Capecchi, M. R. Hoxb8 is required for normal grooming behavior in mice. Neuron 33, 23–34 (2002)
Pogorelov, V. M., Rodriguiz, R. M., Insco, M. L., Caron, M. G. & Wetsel, W. C. Novelty seeking and stereotypic activation of behavior in mice with disruption of the DAT1 gene. Neuropsychopharmacology 30, 1818–1831 (2005)
Weisstaub, N. V. et al. Cortical 5–HT2A receptor signaling modulates anxiety-like behaviors in mice. Science 313, 536–540 (2006)
Bakeman, R. & Gottman, J. M. in Observing Interaction: An Introduction to Sequential Analyses 56–90 (Cambridge Univ. Press, New York, 1997)
Treit, D. & Fundytus, M. Thigmotaxis as a test for anxiolytic activity in rats. Pharmacol. Biochem. Behav. 31, 959–962 (1988)
Crawley, J. N. & Goodwin, F. K. Preliminary report of a simple animal behavior model for the anxiolytic effects of benzodiazepines. Pharmacol. Biochem. Behav. 12, 167–170 (1980)
Feng, G. et al. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28, 41–51 (2000)
Gan, W. B., Grutzendler, J., Wong, W. T., Wong, R. O. & Lichtman, J. W. Multicolor “DiOlistic” labeling of the nervous system using lipophilic dye combinations. Neuron 27, 219–225 (2000)
Lois, C., Hong, E. J., Pease, S., Brown, E. J. & Baltimore, D. Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors. Science 295, 868–872 (2002)
Parker, M. J., Zhao, S., Bredt, D. S., Sanes, J. R. & Feng, G. PSD93 regulates synaptic stability at neuronal cholinergic synapses. J. Neurosci. 24, 378–388 (2004)
Lau, L. F. & Huganir, R. L. Differential tyrosine phosphorylation of N-methyl-D-aspartate receptor subunits. J. Biol. Chem. 270, 20036–20041 (1995)
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.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
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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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