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

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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Figure 1: Facial lesions, excessive grooming and anxiety-like behaviours in Sapap3 -mutant mice.
Figure 2: Fluoxetine treatment alleviates excessive grooming and anxiety-like behaviour.
Figure 3: Altered cortico-striatal synaptic transmission in Sapap3 -mutant mice.
Figure 4: Structural and biochemical analyses of cortico-striatal synapses in Sapap3 -mutant mice.
Figure 5: Lentiviral-mediated rescue of behavioural and synaptic defects in Sapap3 -mutant mice.

References

  1. 1

    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)

    CAS  Article  Google Scholar 

  2. 2

    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)

    Article  Google Scholar 

  3. 3

    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)

    Google Scholar 

  4. 4

    Graybiel, A. M. & Rauch, S. L. Toward a neurobiology of obsessive-compulsive disorder. Neuron 28, 343–347 (2000)

    CAS  Article  Google Scholar 

  5. 5

    Aouizerate, B. et al. Pathophysiology of obsessive-compulsive disorder: a necessary link between phenomenology, neuropsychology, imagery and physiology. Prog. Neurobiol. 72, 195–221 (2004)

    Article  Google Scholar 

  6. 6

    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)

    Article  Google Scholar 

  7. 7

    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)

    CAS  Article  Google Scholar 

  8. 8

    Nestadt, G. et al. A family study of obsessive-compulsive disorder. Arch. Gen. Psychiatry 57, 358–363 (2000)

    CAS  Article  Google Scholar 

  9. 9

    Inouye, E. Similar and dissimilar manifestations of obsessive-compulsive neurosis in monozygotic twins. Am. J. Psychiatry 121, 1171–1175 (1965)

    CAS  Article  Google Scholar 

  10. 10

    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)

    Google Scholar 

  11. 11

    Chakrabarty, K., Bhattacharyya, S., Christopher, R. & Khanna, S. Glutamatergic dysfunction in OCD. Neuropsychopharmacology 30, 1735–1740 (2005)

    CAS  Article  Google Scholar 

  12. 12

    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)

    CAS  Article  Google Scholar 

  13. 13

    Takeuchi, M. et al. SAPAPs. A family of PSD-95/SAP90-associated proteins localized at postsynaptic density. J. Biol. Chem. 272, 11943–11951 (1997)

    CAS  Article  Google Scholar 

  14. 14

    Scannevin, R. H. & Huganir, R. L. Postsynaptic organization and regulation of excitatory synapses. Nature Rev. Neurosci. 1, 133–141 (2000)

    CAS  Article  Google Scholar 

  15. 15

    Kim, E. & Sheng, M. PDZ domain proteins of synapses. Nature Rev. Neurosci. 5, 771–781 (2004)

    CAS  Article  Google Scholar 

  16. 16

    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)

    CAS  Article  Google Scholar 

  17. 17

    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)

    CAS  Article  Google Scholar 

  18. 18

    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)

    CAS  Article  Google Scholar 

  19. 19

    Malinow, R. & Malenka, R. C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002)

    CAS  Article  Google Scholar 

  20. 20

    Prybylowski, K. & Wenthold, R. J. N-Methyl-D-aspartate receptors: subunit assembly and trafficking to the synapse. J. Biol. Chem. 279, 9673–9676 (2004)

    CAS  Article  Google Scholar 

  21. 21

    Nicoll, R. A., Tomita, S. & Bredt, D. S. Auxiliary subunits assist AMPA-type glutamate receptors. Science 311, 1253–1256 (2006)

    ADS  CAS  Article  Google Scholar 

  22. 22

    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)

    ADS  CAS  Article  Google Scholar 

  23. 23

    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)

    CAS  Article  Google Scholar 

  24. 24

    Stocca, G. & Vicini, S. Increased contribution of NR2A subunit to synaptic NMDA receptors in developing rat cortical neurons. J. Physiol. 507, 13–24 (1998)

    CAS  Article  Google Scholar 

  25. 25

    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)

    CAS  Article  Google Scholar 

  26. 26

    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)

    CAS  Article  Google Scholar 

  27. 27

    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)

    CAS  Article  Google Scholar 

  28. 28

    Sans, N. et al. A developmental change in NMDA receptor-associated proteins at hippocampal synapses. J. Neurosci. 20, 1260–1271 (2000)

    CAS  Article  Google Scholar 

  29. 29

    Barria, A. & Malinow, R. Subunit-specific NMDA receptor trafficking to synapses. Neuron 35, 345–353 (2002)

    CAS  Article  Google Scholar 

  30. 30

    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)

    CAS  Article  Google Scholar 

  31. 31

    van Zundert, B., Yoshii, A. & Constantine-Paton, M. Receptor compartmentalization and trafficking at glutamate synapses: a developmental proposal. Trends Neurosci. 27, 428–437 (2004)

    CAS  Article  Google Scholar 

  32. 32

    Valtschanoff, J. G. & Weinberg, R. J. Laminar organization of the NMDA receptor complex within the postsynaptic density. J. Neurosci. 21, 1211–1217 (2001)

    CAS  Article  Google Scholar 

  33. 33

    Day, M. et al. Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models. Nature Neurosci. 9, 251–259 (2006)

    CAS  Article  Google Scholar 

  34. 34

    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)

    CAS  Article  Google Scholar 

  35. 35

    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)

    CAS  Article  Google Scholar 

  36. 36

    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)

    CAS  Article  Google Scholar 

  37. 37

    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)

    CAS  Article  Google Scholar 

  38. 38

    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)

    CAS  Article  Google Scholar 

  39. 39

    Feng, G. et al. Dual requirement for gephyrin in glycine receptor clustering and molybdoenzyme activity. Science 282, 1321–1324 (1998)

    ADS  CAS  Article  Google Scholar 

  40. 40

    Greer, J. M. & Capecchi, M. R. Hoxb8 is required for normal grooming behavior in mice. Neuron 33, 23–34 (2002)

    CAS  Article  Google Scholar 

  41. 41

    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)

    CAS  Article  Google Scholar 

  42. 42

    Weisstaub, N. V. et al. Cortical 5–HT2A receptor signaling modulates anxiety-like behaviors in mice. Science 313, 536–540 (2006)

    ADS  CAS  Article  Google Scholar 

  43. 43

    Bakeman, R. & Gottman, J. M. in Observing Interaction: An Introduction to Sequential Analyses 56–90 (Cambridge Univ. Press, New York, 1997)

    Google Scholar 

  44. 44

    Treit, D. & Fundytus, M. Thigmotaxis as a test for anxiolytic activity in rats. Pharmacol. Biochem. Behav. 31, 959–962 (1988)

    CAS  Article  Google Scholar 

  45. 45

    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)

    Article  Google Scholar 

  46. 46

    Feng, G. et al. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28, 41–51 (2000)

    CAS  Article  Google Scholar 

  47. 47

    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)

    CAS  Article  Google Scholar 

  48. 48

    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)

    ADS  CAS  Article  Google Scholar 

  49. 49

    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)

    CAS  Article  Google Scholar 

  50. 50

    Lau, L. F. & Huganir, R. L. Differential tyrosine phosphorylation of N-methyl-D-aspartate receptor subunits. J. Biol. Chem. 270, 20036–20041 (1995)

    CAS  Article  Google Scholar 

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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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Correspondence to Guoping Feng.

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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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