Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice


Obsessive-compulsive disorder (OCD) is a circuit disorder involving corticostriatal projections, which play a role in motor control. The Sapap3-knockout (KO) mouse is a mouse model to study OCD and recapitulates OCD-like compulsion through excessive grooming behavior, with skin lesions appearing at advanced age. Deficits in corticostriatal control provide a link to the pathophysiology of OCD. However, there remain significant gaps in the characterization of the Sapap3-KO mouse, with respect to age, specificity of synaptic dysfunction, and locomotor phenotype. We therefore investigated the corticostriatal synaptic phenotype of Sapap3-KO mice using patch–clamp slice electrophysiology, in adult mice and with projection specificity. We also analyzed grooming across age and locomotor phenotype with a novel, unsupervised machine learning technique (MoSeq). Increased grooming in Sapap3-KO mice without skin lesions was age independent. Synaptic deficits persisted in adulthood and involved the projections from the motor cortices and cingulate cortex to the dorsolateral and dorsomedial striatum. Decreased synaptic strength was evident at the input from the primary motor cortex by reduction in AMPA receptor function. Hypolocomotion, i.e., slowness of movement, was consistently observed in Sapap3-KO mice. Our findings emphasize the utility of young adult Sapap3-KO mice to investigate corticostriatal synaptic dysfunction in motor control.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Excessive grooming across age in Sapap3-KO mice, but no major genotype effect on PV+ cells in the striatum.
Fig. 2: Corticostriatal synaptic deficits in mice at 10–20 weeks of age.
Fig. 3: Input specificity of corticostriatal synaptic deficits in Sapap3-KO mice.
Fig. 4: Decreased AMPAR currents but no NMDAR subunit differences at the M1/M2-to-DLS synapses in Sapap3-KO mice.
Fig. 5: Locomotion phenotypes are evident in Sapap3-KO mice by conventional behavioral analysis and quantification of sub-second behavioral syllables.


  1. 1.

    Gillan CM, Robbins TW. Goal-directed learning and obsessive-compulsive disorder. Philos Trans R Soc Lond B Biol Sci. 2014;369:1655.

    Google Scholar 

  2. 2.

    Graybiel AM, Rauch SL. Toward a neurobiology of obsessive-compulsive disorder. Neuron. 2000;28:343–7.

    CAS  PubMed  Google Scholar 

  3. 3.

    Park H, Popescu A, Poo MM. Essential role of presynaptic NMDA receptors in activity-dependent BDNF secretion and corticostriatal LTP. Neuron. 2014;84:1009–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Hunnicutt BJ, Jongbloets BC, Birdsong WT, Gertz KJ, Zhong H, Mao T. A comprehensive excitatory input map of the striatum reveals novel functional organization. Elife. 2016;5:e19103.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Graybiel AM, Aosaki T, Flaherty AW, Kimura M. The basal ganglia and adaptive motor control. Science. 1994;265:1826–31.

    CAS  PubMed  Google Scholar 

  6. 6.

    Rasmussen AH, Rasmussen HB, Silahtaroglu A. The DLGAP family: neuronal expression, function and role in brain disorders. Mol Brain. 2017;10:43.

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Zuchner S, Wendland JR, Ashley-Koch AE, Collins AL, Tran-Viet KN, Quinn K, et al. Multiple rare SAPAP3 missense variants in trichotillomania and OCD. Mol Psychiatry. 2009;14:6–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Bienvenu OJ, Wang Y, Shugart YY, Welch JM, Grados MA, Fyer AJ, et al. Sapap3 and pathological grooming in humans: results from the OCD collaborative genetics study. Am J Med Genet B Neuropsychiatr Genet. 2009;150B:710–20.

    CAS  PubMed  Google Scholar 

  9. 9.

    Welch JM, Lu J, Rodriguiz RM, Trotta NC, Peca J, Ding JD, et al. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature.2007;448:894–900.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    van den Boom BJG, Pavlidi P, Wolf CJH, Mooij AH, Willuhn I. Automated classification of self-grooming in mice using open-source software. J Neurosci Methods. 2017;289:48–56.

    PubMed  Google Scholar 

  11. 11.

    Burguiere E, Monteiro P, Feng G, Graybiel AM. Optogenetic stimulation of lateral orbitofronto-striatal pathway suppresses compulsive behaviors. Science 2013;340:1243–6.

    CAS  PubMed  Google Scholar 

  12. 12.

    Ade KK, Wan Y, Hamann HC, O’Hare JK, Guo W, Quian A, et al. Increased metabotropic glutamate receptor 5 signaling underlies obsessive-compulsive disorder-like behavioral and striatal circuit abnormalities in mice. Biol Psychiatry. 2016;80:522–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Manning EE, Dombrovski AY, Torregrossa MM, Ahmari SE. Impaired instrumental reversal learning is associated with increased medial prefrontal cortex activity in Sapap3 knockout mouse model of compulsive behavior. Neuropsychopharmacology. 2019;44:1494–504.

    PubMed  Google Scholar 

  14. 14.

    van den Boom BJG, Mooij AH, Miseviciute I, Denys D, Willuhn I. Behavioral flexibility in a mouse model for obsessive-compulsive disorder: Impaired Pavlovian reversal learning in SAPAP3 mutants. Genes Brain Behav. 2019;18:e12557.

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Hadjas LC, Luscher C, Simmler LD. Aberrant habit formation in the Sapap3-knockout mouse model of obsessive-compulsive disorder. Sci Rep. 2019;9:12061.

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Ehmer I, Feenstra M, Willuhn I, Denys D. Instrumental learning in a mouse model for obsessive-compulsive disorder: impaired habit formation in Sapap3 mutants. Neurobiol Learn Mem. 2020;168:107162.

    CAS  PubMed  Google Scholar 

  17. 17.

    Pinhal CM, van den Boom BJG, Santana-Kragelund F, Fellinger L, Bech P, Hamelink R, et al. Differential effects of deep brain stimulation of the internal capsule and the striatum on excessive grooming in Sapap3 mutant mice. Biol Psychiatry. 2018;84:917–25.

    PubMed  Google Scholar 

  18. 18.

    Todorov G, Mayilvahanan K, Ashurov D, Cunha C. Amelioration of obsessive-compulsive disorder in three mouse models treated with one epigenetic drug: unraveling the underlying mechanism. Sci Rep. 2019;9:8741.

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Chen M, Wan Y, Ade K, Ting J, Feng G, Calakos N. Sapap3 deletion anomalously activates short-term endocannabinoid-mediated synaptic plasticity. J Neurosci. 2011;31:9563–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Wan Y, Feng G, Calakos N. Sapap3 deletion causes mGluR5-dependent silencing of AMPAR synapses. J Neurosci. 2011;31:16685–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Wan Y, Ade KK, Caffall Z, Ilcim Ozlu M, Eroglu C, Feng G, et al. Circuit-selective striatal synaptic dysfunction in the Sapap3 knockout mouse model of obsessive-compulsive disorder. Biol Psychiatry. 2014;75:623–30.

    CAS  PubMed  Google Scholar 

  22. 22.

    Corbit VL, Manning EE, Gittis AH, Ahmari SE. Strengthened inputs from secondary motor cortex to striatum in a mouse model of compulsive behavior. J Neurosci. 2019;39:2965–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Luscher C, Malenka RC. NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Harb Perspect Biol. 2012;4:a005710.

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Kindler S, Rehbein M, Classen B, Richter D, Bockers TM. Distinct spatiotemporal expression of SAPAP transcripts in the developing rat brain: a novel dendritically localized mRNA. Brain Res Mol Brain Res. 2004;126:14–21.

    CAS  PubMed  Google Scholar 

  25. 25.

    Wiltschko AB, Johnson MJ, Iurilli G, Peterson RE, Katon JM, Pashkovski SL, et al. Mapping sub-second structure in mouse behavior. Neuron. 2015;88:1121–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Mathis A, Mamidanna P, Cury KM, Abe T, Murthy VN, Mathis MW, et al. DeepLabCut: markerless pose estimation of user-defined body parts with deep learning. Nat Neurosci. 2018;21:1281–89.

    CAS  PubMed  Google Scholar 

  27. 27.

    Abbas W, Masip Rodo D. Computer methods for automatic locomotion and gesture tracking in mice and small animals for neuroscience applications: a survey. Sensors. 2019;19:3274.

    Google Scholar 

  28. 28.

    Pascoli V, Hiver A, Van Zessen R, Loureiro M, Achargui R, Harada M, et al. Stochastic synaptic plasticity underlying compulsion in a model of addiction. Nature.2018;564:366–71.

    CAS  PubMed  Google Scholar 

  29. 29.

    Paxinos G, Franklin KBJ. The mouse brain in stereotaxic coordinates. Compact 2nd ed. Amsterdam; Boston: Elsevier Academic Press; 2004.

    Google Scholar 

  30. 30.

    Yuan T, Bellone C. Glutamatergic receptors at developing synapses: the role of GluN3A-containing NMDA receptors and GluA2-lacking AMPA receptors. Eur J Pharmaol. 2013;719:107–11.

    CAS  Google Scholar 

  31. 31.

    Ruscio AM, Stein DJ, Chiu WT, Kessler RC. The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry. 2010;15:53–63.

    CAS  PubMed  Google Scholar 

  32. 32.

    Kalueff AV, Stewart AM, Song C, Berridge KC, Graybiel AM, Fentress JC. Neurobiology of rodent self-grooming and its value for translational neuroscience. Nat Rev Neurosci. 2016;17:45–59.

    CAS  PubMed  Google Scholar 

  33. 33.

    Ehmer I, Crown L, van Leeuwen W, Feenstra M, Willuhn I, Denys D. Evidence for distinct forms of compulsivity in the SAPAP3 mutant-mouse model for obsessive-compulsive disorder. eNeuro. 2020;7:ENEURO.0245-19.2020.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Albin RL, Young AB, Penney JB. The functional anatomy of basal ganglia disorders. Trends Neurosci. 1989;12:366–75.

    CAS  PubMed  Google Scholar 

  35. 35.

    Wood J, LaPalombara Z, Ahmari SE. Monoamine abnormalities in the SAPAP3 knockout model of obsessive-compulsive disorder-related behaviour. Philos Trans R Soc Lond B Biol Sci. 2018;373:20170023.

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Mahgoub M, Adachi M, Suzuki K, Liu X, Kavalali ET, Chahrour MH, et al. MeCP2 and histone deacetylases 1 and 2 in dorsal striatum collectively suppress repetitive behaviors. Nat Neurosci. 2016;19:1506–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Hirjak D, Meyer-Lindenberg A, Fritze S, Sambataro F, Kubera KM, Wolf RC. Motor dysfunction as research domain across bipolar, obsessive-compulsive and neurodevelopmental disorders. Neurosci Biobehav Rev. 2018;95:315–35.

    PubMed  Google Scholar 

  38. 38.

    Bihari K, Pato MT, Hill JL, Murphy DL. Neurologic soft signs in obsessive-compulsive disorder. Arch Gen Psychiatry. 1991;48:278–9.

    CAS  PubMed  Google Scholar 

  39. 39.

    Hollander E, Schiffman E, Cohen B, Rivera-Stein MA, Rosen W, Gorman JM, et al. Signs of central nervous system dysfunction in obsessive-compulsive disorder. Arch Gen Psychiatry. 1990;47:27–32.

    CAS  PubMed  Google Scholar 

  40. 40.

    Mergl R, Mavrogiorgou P, Juckel G, Zaudig M, Hegerl U. Effects of sertraline on kinematic aspects of hand movements in patients with obsessive-compulsive disorder. Psychopharmacol. 2004;171:179–85.

    CAS  Google Scholar 

  41. 41.

    Kuelz AK, Hohagen F, Voderholzer U. Neuropsychological performance in obsessive-compulsive disorder: a critical review. Biol Psychol. 2004;65:185–236.

    PubMed  Google Scholar 

  42. 42.

    Snyder HR, Kaiser RH, Warren SL, Heller W. Obsessive-compulsive disorder is associated with broad impairments in executive function: a meta-analysis. Clin Psychol Sci. 2015;3:301–30.

    PubMed  Google Scholar 

  43. 43.

    Tukel R, Gurvit H, Ertekin BA, Oflaz S, Ertekin E, Baran B, et al. Neuropsychological function in obsessive-compulsive disorder. Compr Psychiatry. 2012;53:167–75.

    PubMed  Google Scholar 

  44. 44.

    Hymas N, Lees A, Bolton D, Epps K, Head D. The neurology of obsessional slowness. Brain. 1991;114:2203–33.

    PubMed  Google Scholar 

  45. 45.

    Benzina N, Mallet L, Burguiere E, N’Diaye K, Pelissolo A. Cognitive dysfunction in obsessive-compulsive disorder. Curr Psychiatry Rep. 2016;18:80.

    PubMed  Google Scholar 

  46. 46.

    Gremel CM, Costa RM. Premotor cortex is critical for goal-directed actions. Front Comput Neurosci. 2013;7:110.

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Gremel CM, Chancey JH, Atwood BK, Luo G, Neve R, Ramakrishnan C, et al. Endocannabinoid modulation of orbitostriatal circuits gates habit formation. Neuron. 2016;90:1312–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Simmler LD, Ozawa T. Neural circuits in goal-directed and habitual behavior: Implications for circuit dysfunction in obsessive-compulsive disorder. Neurochem Int. 2019;129:104464.

    CAS  PubMed  Google Scholar 

  49. 49.

    Ahmari SE, Spellman T, Douglass NL, Kheirbek MA, Simpson HB, Deisseroth K, et al. Repeated cortico-striatal stimulation generates persistent OCD-like behavior. Science.2013;340:1234–9.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


The authors would like to thank Agnès Hiver and Sébastien Pellat for excellent laboratory assistance and technical support.

Author information




LDS, LCH, JC, MCC, and VP performed experiments. MMS implemented and performed MoSeq analysis. LDS and CL conceptualized and supervised the study. LDS wrote the paper. All authors contributed to and approved the final paper.

Corresponding author

Correspondence to Linda D. Simmler.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hadjas, L.C., Schartner, M.M., Cand, J. et al. Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice. Neuropsychopharmacol. (2020).

Download citation