Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Lower excitatory synaptic gene expression in orbitofrontal cortex and striatum in an initial study of subjects with obsessive compulsive disorder

Molecular Psychiatry volume 26, pages 986–998 (2021)Cite this article

Subjects

Abstract

Obsessive compulsive disorder (OCD) is a severe illness that affects 2–3% of people worldwide. OCD neuroimaging studies have consistently shown abnormal activity in brain regions involved in decision-making (orbitofrontal cortex [OFC]) and action selection (striatum). However, little is known regarding molecular changes that may contribute to abnormal function. We therefore examined expression of synaptic genes in post-mortem human brain samples of these regions from eight pairs of unaffected comparison and OCD subjects. Total grey matter tissue samples were obtained from medial OFC (BA11), lateral OFC (BA47), head of caudate, and nucleus accumbens (NAc). Quantitative polymerase chain reaction (qPCR) was then performed on a panel of transcripts encoding proteins related to excitatory synaptic structure, excitatory synaptic receptors/transporters, and GABA synapses. Relative to unaffected comparison subjects, OCD subjects had significantly lower levels of several transcripts related to excitatory signaling in both cortical and striatal regions. However, a majority of transcripts encoding excitatory synaptic proteins were lower in OFC but not significantly different in striatum of OCD subjects. Composite transcript level measures supported these findings by revealing that reductions in transcripts encoding excitatory synaptic structure proteins and excitatory synaptic receptors/transporters occurred primarily in OFC of OCD subjects. In contrast, transcripts associated with inhibitory synaptic neurotransmission showed minor differences between groups. The observed lower levels of multiple glutamatergic transcripts across both medial and lateral OFC may suggest an upstream causal event. Together, these data provide the first evidence of molecular abnormalities in brain regions consistently implicated in OCD human imaging studies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Archiv Gen Psychiatry. 2005;62:593–602.

    Google Scholar 

  2. Eaton WW, Martins SS, Nestadt G, Bienvenu OJ, Clarke D, Alexandre P. The burden of mental disorders. Epidemiol Rev. 2008;30:1–14.

    PubMed  PubMed Central  Google Scholar 

  3. Bollini P, Pampallona S, Tibaldi G, Kupelnick B, Munizza C. Effectiveness of antidepressants. Meta-analysis of dose-effect relationships in randomised clinical trials. Br J Psychiatry. 1999;174:297–303.

    CAS  Google Scholar 

  4. Pigott TA, Seay SM. A review of the efficacy of selective serotonin reuptake inhibitors in obsessive-compulsive disorder. J Clin Psychiatry. 1999;60:101–6.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  6. Rotge JY, Guehl D, Dilharreguy B, Tignol J, Bioulac B, Allard M, et al. Meta-analysis of brain volume changes in obsessive-compulsive disorder. Biol Psychiatry. 2009;65:75–83.

    PubMed  Google Scholar 

  7. Pauls DL, Abramovitch A, Rauch SL, Geller DA. Obsessive-compulsive disorder: an integrative genetic and neurobiological perspective. Nat Rev Neurosci. 2014;15:410–24.

    CAS  PubMed  Google Scholar 

  8. Harrison BJ, Soriano-Mas C, Pujol J, Ortiz H, Lopez-Sola M, Hernandez-Ribas R, et al. Altered corticostriatal functional connectivity in obsessive-compulsive disorder. Arch Gen Psychiatry. 2009;66:1189–200.

    PubMed  Google Scholar 

  9. Fitzgerald KD, Welsh RC, Stern ER, Angstadt M, Hanna GL, Abelson JL, et al. Developmental alterations of frontal-striatal-thalamic connectivity in obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry. 2011;50:938–48 e3.

    PubMed  PubMed Central  Google Scholar 

  10. Menzies L, Chamberlain SR, Laird AR, Thelen SM, Sahakian BJ, Bullmore ET. Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofronto-striatal model revisited. Neurosci Biobehav Rev. 2008;32:525–49.

    PubMed  Google Scholar 

  11. Whiteside SP, Port JD, Abramowitz JS. A meta-analysis of functional neuroimaging in obsessive-compulsive disorder. Psychiatry Res. 2004;132:69–79.

    PubMed  Google Scholar 

  12. Rauch SL, Shin LM, Dougherty DD, Alpert NM, Fischman AJ, Jenike MA. Predictors of fluvoxamine response in contamination-related obsessive compulsive disorder: a PET symptom provocation study. Neuropsychopharmacology. 2002;27:782–91.

    CAS  PubMed  Google Scholar 

  13. Rauch SL, Dougherty DD, Malone D, Rezai A, Friehs G, Fischman AJ, et al. A functional neuroimaging investigation of deep brain stimulation in patients with obsessive-compulsive disorder. J Neurosurg. 2006;104:558–65.

    PubMed  Google Scholar 

  14. Bourne SK, Eckhardt CA, Sheth SA, Eskandar EN. Mechanisms of deep brain stimulation for obsessive compulsive disorder: effects upon cells and circuits. Front Integr Neurosci. 2012;6:29.

    PubMed  PubMed Central  Google Scholar 

  15. 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 

  16. 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 

  17. Taylor S. Etiology of obsessions and compulsions: a meta-analysis and narrative review of twin studies. Clin Psychol Rev. 2011;31:1361–72.

    PubMed  Google Scholar 

  18. Stewart SE, Yu D, Scharf JM, Neale BM, Fagerness JA, Mathews CA, et al. Genome-wide association study of obsessive-compulsive disorder. Mol Psychiatry. 2013;18:788–98.

    CAS  PubMed  Google Scholar 

  19. Mattheisen M, Samuels JF, Wang Y, Greenberg BD, Fyer AJ, McCracken JT, et al. Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS. Mol Psychiatry. 2015;20:337–44.

    CAS  PubMed  Google Scholar 

  20. Takahashi H, Craig AM. Protein tyrosine phosphatases PTPdelta, PTPsigma, and LAR: presynaptic hubs for synapse organization. Trends Neurosci. 2013;36:522–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Dickel DE, Veenstra-VanderWeele J, Cox NJ, Wu X, Fischer DJ, Van Etten-Lee M, et al. Association testing of the positional and functional candidate gene SLC1A1/EAAC1 in early-onset obsessive-compulsive disorder. Arch Gen Psychiatry. 2006;63:778–85.

    CAS  PubMed  Google Scholar 

  22. Arnold PD, Sicard T, Burroughs E, Richter MA, Kennedy JL. Glutamate transporter gene SLC1A1 associated with obsessive-compulsive disorder. Arch Gen Psychiatry. 2006;63:769–76.

    CAS  PubMed  Google Scholar 

  23. Porton B, Greenberg BD, Askland K, Serra LM, Gesmonde J, Rudnick G, et al. Isoforms of the neuronal glutamate transporter gene, SLC1A1/EAAC1, negatively modulate glutamate uptake: relevance to obsessive-compulsive disorder. Transl Psychiatry. 2013;3:e259.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Samuels J, Wang Y, Riddle MA, Greenberg BD, Fyer AJ, McCracken JT, et al. Comprehensive family-based association study of the glutamate transporter gene SLC1A1 in obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet. 2011;156B:472–7.

    PubMed  Google Scholar 

  25. Shugart YY, Wang Y, Samuels JF, Grados MA, Greenberg BD, Knowles JA, et al. A family-based association study of the glutamate transporter gene SLC1A1 in obsessive-compulsive disorder in 378 families. Am J Med Genet B Neuropsychiatr Genet. 2009;150B:886–92.

    CAS  PubMed  Google Scholar 

  26. Stewart SE, Fagerness JA, Platko J, Smoller JW, Scharf JM, Illmann C, et al. Association of the SLC1A1 glutamate transporter gene and obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet. 2007;144B:1027–33.

    CAS  PubMed  Google Scholar 

  27. Zike ID, Chohan MO, Kopelman JM, Krasnow EN, Flicker D, Nautiyal KM, et al. OCD candidate gene SLC1A1/EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior. Proc Natl Acad Sci USA. 2017;114:5719–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Welch JM, Lu J, Rodriguiz RM, Trotta NC, Peca J, Ding J-DD, 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 

  29. Shmelkov SV, Hormigo A, Jing D, Proenca CC, Bath KG, Milde T, et al. Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice. Nat Med. 2010;16:598–602.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Simpson HB, Shungu DC, Bender J, Mao X, Xu X, Slifstein M, et al. Investigation of cortical glutamate-glutamine and gamma-aminobutyric acid in obsessive-compulsive disorder by proton magnetic resonance spectroscopy. Neuropsychopharmacology. 2012;37:2684–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Rodriguez CI, Kegeles LS, Levinson A, Ogden RT, Mao X, Milak MS, et al. In vivo effects of ketamine on glutamate-glutamine and gamma-aminobutyric acid in obsessive-compulsive disorder: Proof of concept. Psychiatry Res. 2015;233:141–7.

    PubMed  PubMed Central  Google Scholar 

  32. Richter MA, de Jesus DR, Hoppenbrouwers S, Daigle M, Deluce J, Ravindran LN, et al. Evidence for cortical inhibitory and excitatory dysfunction in obsessive compulsive disorder. Neuropsychopharmacology. 2012;37:1144–51.

    CAS  PubMed  Google Scholar 

  33. Du JC, Chiu TF, Lee KM, Wu HL, Yang YC, Hsu SY, et al. Tourette syndrome in children: an updated review. Pediatr Neonatol. 2010;51:255–64.

    PubMed  Google Scholar 

  34. Kalanithi PS, Zheng W, Kataoka Y, DiFiglia M, Grantz H, Saper CB, et al. Altered parvalbumin-positive neuron distribution in basal ganglia of individuals with Tourette syndrome. Proc Natl Acad Sci USA. 2005;102:13307–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Kataoka Y, Kalanithi PS, Grantz H, Schwartz ML, Saper C, Leckman JF, et al. Decreased number of parvalbumin and cholinergic interneurons in the striatum of individuals with Tourette syndrome. J Comp Neurol. 2010;518:277–91.

    PubMed  PubMed Central  Google Scholar 

  36. Xu M, Li L, Pittenger C. Ablation of fast-spiking interneurons in the dorsal striatum, recapitulating abnormalities seen post-mortem in Tourette syndrome, produces anxiety and elevated grooming. Neuroscience. 2016;324:321–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Jaffe AE, Deep-Soboslay A, Tao R, Hauptman DT, Kaye WH, Arango V, et al. Genetic neuropathology of obsessive psychiatric syndromes. Transl Psychiatry. 2014;4:e432.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Breiter HC, Rauch SL, Kwong KK, Baker JR, Weisskoff RM, Kennedy DN, et al. Functional magnetic resonance imaging of symptom provocation in obsessive-compulsive disorder. Arch Gen Psychiatry. 1996;53:595–606.

    CAS  PubMed  Google Scholar 

  39. Rauch SL, Savage CR, Alpert NM, Fischman AJ, Jenike MA. The functional neuroanatomy of anxiety: a study of three disorders using positron emission tomography and symptom provocation. Biol Psychiatry. 1997;42:446–52.

    CAS  PubMed  Google Scholar 

  40. Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3:RESEARCH0034.

    PubMed  PubMed Central  Google Scholar 

  41. Benjamini YHY. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Royal Statis Soc Series B.1995;57:289–300.

    Google Scholar 

  42. Vigneault E, Poirel O, Riad M, Prud’homme J, Dumas S, Turecki G, et al. Distribution of vesicular glutamate transporters in the human brain. Front Neuroanat. 2015;9:23.

    PubMed  PubMed Central  Google Scholar 

  43. Bernacer J, Prensa L, Gimenez-Amaya JM. Distribution of GABAergic interneurons and dopaminergic cells in the functional territories of the human striatum. PLoS ONE. 2012;7:e30504.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 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 

  45. Boardman L, van der Merwe L, Lochner C, Kinnear CJ, Seedat S, Stein DJ, et al. Investigating SAPAP3 variants in the etiology of obsessive-compulsive disorder and trichotillomania in the South African white population. Compr Psychiatry. 2011;52:181–7.

    PubMed  Google Scholar 

  46. 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 

  47. Atmaca M, Yildirim BH, Ozdemir BH, Aydin BA, Tezcan AE, Ozler AS. Volumetric MRI assessment of brain regions in patients with refractory obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:1051–7.

    PubMed  Google Scholar 

  48. Atmaca M, Yildirim H, Ozdemir H, Tezcan E, Poyraz AK. Volumetric MRI study of key brain regions implicated in obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:46–52.

    PubMed  Google Scholar 

  49. Selemon LD, Goldman-Rakic PS. The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry. 1999;45:17–25.

    CAS  PubMed  Google Scholar 

  50. Penzes P, Cahill ME, Jones KA, VanLeeuwen JE, Woolfrey KM. Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci. 2011;14:285–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Glausier JR, Lewis DA. Dendritic spine pathology in schizophrenia. Neuroscience. 2013;251:90–107.

    CAS  PubMed  Google Scholar 

  52. Wu K, Hanna GL, Easter P, Kennedy JL, Rosenberg DR, Arnold PD. Glutamate system genes and brain volume alterations in pediatric obsessive-compulsive disorder: A preliminary study. Psychiatry Res Neuroimaging. 2013;211:214–20.

    CAS  PubMed  Google Scholar 

  53. Abelson JF. Sequence Variants in SLITRK1 Are Associated with Tourette's Syndrome. Science. 2005;310:317–20.

    CAS  PubMed  Google Scholar 

  54. Ortiz AE, Gassó P, Mas S, Falcon C, Bargalló N, Lafuente A, et al. Association between genetic variants of serotonergic and glutamatergic pathways and the concentration of neurometabolites of the anterior cingulate cortex in paediatric patients with obsessive–compulsive disorder. World J Biol Psychiatry. 2015;17:394–404.

    PubMed  Google Scholar 

  55. Lennington JB, Coppola G, Kataoka-Sasaki Y, Fernandez TV, Palejev D, Li Y, et al. Transcriptome Analysis of the Human Striatum in Tourette Syndrome. Biol Psychiatry. 2016;79:372–82.

    CAS  PubMed  Google Scholar 

  56. Mas S, Pagerols M, Gassó P, Ortiz A, Rodriguez N, Morer A, et al. Role of and genes in early-onset obsessive-compulsive disorder: results from transmission disequilibrium study. Genes Brain Behav. 2014;13:409–17.

    CAS  Google Scholar 

  57. Zuchner S, Cuccaro ML, Tran-Viet KN, Cope H, Krishnan RR, Pericak-Vance MA, et al. SLITRK1 mutations in Trichotillomania. Mol Psychiatry. 2006;11:888–9.

    Google Scholar 

  58. Arnold PD, Rosenberg DR, Mundo E, Tharmalingam S, Kennedy JL, Richter MA. Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study. Psychopharmacology. 2004;174:530–8.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would first like to thank the subjects and their families for the generous gift of brain donation. Tissue from some subjects was obtained from the NIH NeuroBioBank at the University of Pittsburgh Brain Tissue Donation Program. We would also like to thank Kelly Rogers for her assistance with subject selection and tissue blocking, and Dr. Sue Johnston for her assistance with clinical assessments of post-mortem subjects. Funding support was provided by the Brain Research Foundation Fay and Frank Seed Grant (SEA, SCP).

Author information

Authors and Affiliations

  1. Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

    Sean C. Piantadosi, David A. Lewis & Susanne E. Ahmari

  2. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    Sean C. Piantadosi, Brittany L. Chamberlain, Jill R. Glausier, David A. Lewis & Susanne E. Ahmari

Authors
  1. Sean C. Piantadosi
    View author publications

    Search author on:PubMed Google Scholar

  2. Brittany L. Chamberlain
    View author publications

    Search author on:PubMed Google Scholar

  3. Jill R. Glausier
    View author publications

    Search author on:PubMed Google Scholar

  4. David A. Lewis
    View author publications

    Search author on:PubMed Google Scholar

  5. Susanne E. Ahmari
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Susanne E. Ahmari.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Piantadosi, S.C., Chamberlain, B.L., Glausier, J.R. et al. Lower excitatory synaptic gene expression in orbitofrontal cortex and striatum in an initial study of subjects with obsessive compulsive disorder. Mol Psychiatry 26, 986–998 (2021). https://doi.org/10.1038/s41380-019-0431-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41380-019-0431-3

This article is cited by

Search

Advanced search

Quick links