Increased Metabotropic Glutamate Receptor 5 Signaling Underlies Obsessive-Compulsive Disorder-like Behavioral and Striatal Circuit Abnormalities in Mice
Open accessAbstract
Background Development of treatments for obsessive-compulsive disorder (OCD) is hampered by a lack of mechanistic understanding about this prevalent neuropsychiatric condition. Although circuit changes such as elevated frontostriatal activity are linked to OCD, the underlying molecular signaling that drives OCD-related behaviors remains largely unknown. Here, we examine the significance of type 5 metabotropic glutamate receptors (mGluR5s) for behavioral and circuit abnormalities relevant to OCD.Methods Sapap3 knockout (KO) mice treated acutely with an mGluR5 antagonist were evaluated for OCD-relevant phenotypes of self-grooming, anxiety-like behaviors, and increased striatal activity. The role of mGluR5 in the striatal circuit abnormalities of Sapap3 KO mice was further explored using two-photon calcium imaging to monitor striatal output from the direct and indirect pathways. A contribution of constitutive signaling to increased striatal mGluR5 activity in Sapap3 KO mice was investigated using pharmacologic and biochemical approaches. Finally, sufficiency of mGluR5 to drive OCD-like behavior in wild-type mice was tested by potentiating mGluR5 with a positive allosteric modulator.Results Excessive mGluR5 signaling underlies OCD-like behaviors and striatal circuit abnormalities in Sapap3 KO mice. Accordingly, enhancing mGluR5 activity acutely recapitulates these behavioral phenotypes in wild-type mice. In Sapap3 KO mice, elevated mGluR5 signaling is associated with constitutively active receptors and increased and imbalanced striatal output that is acutely corrected by antagonizing striatal mGluR5.Conclusions These findings demonstrate a causal role for increased mGluR5 signaling in driving striatal output abnormalities and behaviors with relevance to OCD and show the tractability of acute mGluR5 inhibition to remedy circuit and behavioral abnormalities.
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Sapap3-KO mice exhibit anxiety-like behavior.
“Such phenotypes are excessive grooming [9][10][11], anxiety-like behavior [9,12], behavioral inflexibility [13,14], and deficits in the balance of habitual and goal-directed behavior [15,16].”
From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [12]
Excessive grooming in Sapap3-KO mice has been consistently observed across experimental conditions, including testing during light cycle and during the dark period.
“In contrast, excessive grooming in Sapap3-KO mice has been consistently observed across experimental conditions, including testing during light cycle [9,12,13] and during the dark period [9,10,17,33], which shows the robustness of the phenotype.”
From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [12]
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The functional anatomy of basal ganglia disorders
Albin, R. L., Young, A. B., & Penney, J. B. (1989) · Trends in Neurosciences · doi:10.1016/0166-2236(89)90074-x · Cited by 5,353 · see citing works
Primate models of movement disorders of basal ganglia origin
DeLong, M. R. (1990) · Trends in Neurosciences · doi:10.1016/0166-2236(90)90110-v · Cited by 3,824 · see citing works
Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry
Kravitz, A. V., Freeze, B. S., Parker, P. R. L., Kay, K., Thwin, M. T., Deisseroth, K., & Kreitzer, A. C. (2010) · Nature · doi:10.1038/nature09159 · Cited by 1,885 · see citing works
Distinct roles for direct and indirect pathway striatal neurons in reinforcement
Kravitz, A. V., Tye, L. D., & Kreitzer, A. C. (2012) · Nature Neuroscience · doi:10.1038/nn.3100 · Cited by 972 · see citing works
Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward
Lobo, M. K., Covington, H. E., Chaudhury, D., Friedman, A. K., Sun, H., Damez-Werno, D., Dietz, D. M., Zaman, S., Koo, J. W., Kennedy, P. J., et al. (2010) · Science · doi:10.1126/science.1188472 · Cited by 880 · see citing works
Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice
Welch, J. M., Lu, J., Rodriguiz, R. M., Trotta, N. C., Peca, J., Ding, J.-D., Feliciano, C., Chen, M., Adams, J. P., Luo, J., et al. (2007) · Nature · doi:10.1038/nature06104 · Cited by 852 · see citing works
Self-citationObsessive-compulsive disorder: An integrative genetic and neurobiological perspective
Pauls, D. L., Abramovitch, A., Rauch, S. L., & Geller, D. A. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3746 · Cited by 793 · see citing works
Shepherd, J. K., Grewal, S. S., Fletcher, A., Bill, D. J., & Dourish, C. T. (1994) · Psychopharmacology · doi:10.1007/bf02244871 · Cited by 739 · see citing works
Cortico–basal ganglia circuit mechanism for a decision threshold in reaction time tasks
Lo, C.-C., & Wang, X.-J. (2006) · Nature Neuroscience · doi:10.1038/nn1722 · Cited by 505 · see citing works
Repeated cortico-striatal stimulation generates persistent OCD-like behavior
Ahmari, S. E., Spellman, T., Douglass, N. L., Kheirbek, M. A., Simpson, H. B., Deisseroth, K., Gordon, J. A., & Hen, R. (2013) · Science · doi:10.1126/science.1234733 · Cited by 502 · cited 4× · see citing works
“Increased striatal activity has been associated with OCD behaviors in both clinical populations (5–7) and animal models (3,4).”
BackgroundInfluentialOptogenetic stimulation of lateral orbitofronto-striatal pathway suppresses compulsive behaviors
Burguière, E., Monteiro, P., Feng, G., & Graybiel, A. M. (2013) · Science · doi:10.1126/science.1232380 · Cited by 457 · see citing works
Silverman, J. L., Tolu, S. S., Barkan, C. L., & Crawley, J. N. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2009.201 · Cited by 438 · see citing works
The Epidemiology of Obsessive-Compulsive Disorder in Children and Adolescents
Zohar, A. H. (1999) · Child and Adolescent Psychiatric Clinics of North America · doi:10.1016/s1056-4993(18)30163-9 · Cited by 431 · see citing works
Mallet, N. P., Ballion, B., Moine, C. L., & Gonon, F. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.4439-05.2006 · Cited by 413 · see citing works
Ango, F., Prézeau, L., Müller, T. H., Tu, J. C., Xiao, B., Worley, P. F., Pin, J., Bockaert, J., & Fagni, L. (2001) · Nature · doi:10.1038/35082096 · Cited by 410 · see citing works
Transient stimulation of distinct subpopulations of striatal neurons mimics changes in action value
Tai, L.-H., Lee, A. M., Benavidez, N., Bonci, A., & Wilbrecht, L. (2012) · Nature Neuroscience · doi:10.1038/nn.3188 · Cited by 399 · see citing works
Genome-wide association study of obsessive-compulsive disorder
Stewart, S. E., Yu, D., Scharf, J. M., Neale, B. M., Fagerness, J. A., Mathews, C. A., Arnold, P. D., Evans, P. D., Gamazon, E. R., Osiecki, L., et al. (2013) · Molecular Psychiatry · doi:10.1038/mp.2012.85 · Cited by 384 · see citing works
Reassessing Models of Basal Ganglia Function and Dysfunction
Nelson, A., & Kreitzer, A. C. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-013916 · Cited by 338 · see citing works
Evidence-based pharmacotherapy of obsessive-compulsive disorder
Fineberg, N. A., Brown, A., Reghunandanan, S., & Pampaloni, I. (2012) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145711001829 · Cited by 336 · see citing works
Maltby, N., Tolin, D. F., Worhunsky, P., O'Keefe, T. M., & Kiehl, K. A. (2005) · NeuroImage · doi:10.1016/j.neuroimage.2004.08.041 · Cited by 331 · see citing works
Pisani, A., Gubellini, P., Bonsi, P., Conquet, F., Picconi, B., Centonze, D., Bernardi, G., & Calabresi, P. (2001) · Neuroscience · doi:10.1016/s0306-4522(01)00297-4 · Cited by 311 · see citing works
Role for metabotropic glutamate receptor 5 (mGluR5) in the pathogenesis of fragile X syndrome
Dölen, G., & Bear, M. F. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2008.150722 · Cited by 278 · see citing works
Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome
Ronesi, J. A., Collins, K. A., Hays, S. A., Tsai, N.-P., Guo, W., Birnbaum, S. G., Hu, J.-H., Worley, P. F., Gibson, J. R., & Huber, K. M. (2012) · Nature Neuroscience · doi:10.1038/nn.3033 · Cited by 251 · see citing works
Self-citationMao, L., Yang, L., Tang, Q., Samdani, S., Zhang, G., & Wang, J. Q. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.4360-04.2005 · Cited by 250 · see citing works
Rodgers, R. J., & Shepherd, J. K. (1993) · Psychopharmacology · doi:10.1007/bf02245704 · Cited by 221 · see citing works
mGluR5 Has a Critical Role in Inhibitory Learning
Xu, J., Zhu, Y., Contractor, A., & Heinemann, S. F. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.5716-08.2009 · Cited by 221 · see citing works
Early hyperactivity and precocious maturation of corticostriatal circuits in Shank3B−/− mice
Peixoto, R. T., Wang, W., Croney, D. M., Kozorovitskiy, Y., & Sabatini, B. L. (2016) · Nature Neuroscience · doi:10.1038/nn.4260 · Cited by 219 · see citing works
Evidence-based pharmacotherapy of obsessive–compulsive disorder
Fineberg, N. A., & Gale, T. M. (2005) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145704004675 · Cited by 213 · see citing works
<i>Sapap3</i> and pathological grooming in humans: Results from the OCD collaborative genetics study
Bienvenu, O. J., Wang, Y., Shugart, Y. Y., Welch, J. M., Grados, M. A., Fyer, A. J., Rauch, S. L., McCracken, J. T., Rasmussen, S. A., Murphy, D. L., et al. (2009) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30897 · Cited by 207 · see citing works
Multiple rare SAPAP3 missense variants in trichotillomania and OCD
Züchner, S., Wendland, J. R., Ashley-Koch, A. E., Collins, A. L., Tran-Viet, K. N., Quinn, K., Timpano, K. C., Cuccaro, M. L., Pericak-Vance, M. A., Steffens, D. C., et al. (2009) · Molecular Psychiatry · doi:10.1038/mp.2008.83 · Cited by 196 · see citing works
Mehta, M. V., Gandal, M. J., & Siegel, S. J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026077 · Cited by 182 · see citing works
Rodriguez, A. L., Grier, M. D., Jones, C. K., Herman, E. J., Kane, A. S., Smith, R. L., Williams, R. D., Zhou, Y., Marlo, J. E., Days, E., et al. (2010) · Molecular Pharmacology · doi:10.1124/mol.110.067207 · Cited by 178 · see citing works
Self-citationAde, K. K., Wan, Y., Chen, M., Gloss, B. R., & Calakos, N. (2011) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2011.00032 · Cited by 175 · see citing works
Self-citationActivation of Group I mGluRs Is Necessary for Induction of Long-Term Depression at Striatal Synapses
Sung, K.-W., Choi, S., & Lovinger, D. M. (2001) · Journal of Neurophysiology · doi:10.1152/jn.2001.86.5.2405 · Cited by 161 · see citing works
Pathway-Specific Striatal Substrates for Habitual Behavior
O’Hare, J. K., Ade, K. K., Sukharnikova, T., Hooser, S. D. V., Palmeri, M. L., Yin, H. H., & Calakos, N. (2016) · Neuron · doi:10.1016/j.neuron.2015.12.032 · Cited by 148 · see citing works
Self-citationKalueff, A. V., & Tuohimaa, P. (2005) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2004.11.054 · Cited by 142 · see citing works
Giuffrida, R., Musumeci, S. A., D’Antoni, S., Bonaccorso, C. M., Giuffrida‐Stella, A. M., Oostra, B. A., & Catania, M. V. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.0932-05.2005 · Cited by 137 · see citing works
Baxter, L. R., Saxena, S., Brody, A., Ackermann, R., Colgan, M., Schwartz, Allen-Martinez, Z., Fuster, J. M., & Me, P. (1996) · PubMed · doi:10.1053/scnp00100032 · Cited by 134 · see citing works
Neuronal Correlates of Obsessions in the Caudate Nucleus
Guehl, D., Benazzouz, A., Aouizerate, B., Cuny, E., Rotgé, J., Rougier, A., Tignol, J., Bioulac, B. H., & Burbaud, P. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2007.06.023 · Cited by 124 · see citing works
Welch, J. M., Wang, D., & Feng, G. (2004) · The Journal of Comparative Neurology · doi:10.1002/cne.20060 · Cited by 115 · see citing works
Hansen, E. S., Hasselbalch, S. G., Law, I. G., & Bolwig, T. G. (2002) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145701002681 · Cited by 114 · see citing works
Wong, D. F., Waterhouse, R. N., Kuwabara, H., Kim, J., Brašić, J. R., Chamroonrat, W., Stabins, M., Holt, D. P., Dannals, R. F., Hamill, T. G., et al. (2013) · Journal of Nuclear Medicine · doi:10.2967/jnumed.112.107995 · Cited by 105 · see citing works
<i>Sapap3</i> Deletion Causes mGluR5-Dependent Silencing of AMPAR Synapses
Wan, Y., Feng, G., & Calakos, N. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.2533-11.2011 · Cited by 101 · see citing works
Self-citationKantak, P. A., Bobrow, D. N., & Nyby, J. (2013) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000013 · Cited by 101 · see citing works
Egashira, N., Okuno, R., Harada, S., Matsushita, M., Mishima, K., Iwasaki, K., Nishimura, R., Oishi, R., & Fujiwara, M. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.01.035 · Cited by 95 · see citing works
Metabotropic glutamate receptor 5 in the pathology and treatment of schizophrenia
Matosin, N., & Newell, K. A. (2012) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2012.12.005 · Cited by 89 · see citing works
Sapap3 Deletion Anomalously Activates Short-Term Endocannabinoid-Mediated Synaptic Plasticity
Chen, M., Wan, Y., Ade, K., Ting, J., Feng, G., & Calakos, N. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.1701-11.2011 · Cited by 82 · see citing works
Self-citationDirect-Pathway Striatal Neurons Regulate the Retention of Decision-Making Strategies
Ferguson, S. M., Phillips, P. E. M., Roth, B. L., Wess, J., & Neumaier, J. F. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.4783-12.2013 · Cited by 78 · see citing works
Bonsi, P., Cuomo, D., Persis, C. D., Centonze, D., Bernardi, G., Calabresi, P., & Pisani, A. (2005) · Neuropharmacology · doi:10.1016/j.neuropharm.2005.05.012 · Cited by 75 · see citing works
Kalinichev, M., Poul, E. L., Boléa, C., Girard, F., Campo, B., Fonsi, M., Royer-Urios, I., Browne, S. E., Uslaner, J. M., Davis, M. J., et al. (2014) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.114.214437 · Cited by 70 · see citing works
Aguilar‐Valles, A., Matta‐Camacho, E., Khoutorsky, A., Gkogkas, C. G., Nader, K., Lacaille, J., & Sonenberg, N. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.4615-14.2015 · Cited by 62 · see citing works
Chronic in vivo multi-circuit neurophysiological recordings in mice
Dzirasa, K., Fuentes, R., Kumar, S., Potes, J. M., & Nicolelis, M. A. L. (2010) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2010.11.014 · Cited by 57 · see citing works
Self-citationDoria, J. G., de Souza, J. M., Andrade, J. N., Rodrigues, H. A., Guimaraes, I. M., Carvalho, T. G., Guatimosim, C., Dobránsky, T., & Ribeiro, F. M. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.021 · Cited by 54 · see citing works
Metabotropic glutamate receptor 5 binding in patients with obsessive-compulsive disorder
Akkus, F., Terbeck, S., Ametamey, S. M., Rufer, M., Treyer, V., Burger, C., Johayem, A., Gomez‐Mancilla, B., Sóvágó, J., Buck, A., et al. (2014) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145714000716 · Cited by 54 · see citing works
D’Ascenzo, M., Podda, M. V., Fellin, T., Azzena, G. B., Haydon, P. G., & Grassi, C. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2009.172593 · Cited by 49 · see citing works
Rook, J. M., Tantawy, M. N., Ansari, M. S., Felts, A. S., Stauffer, S. R., Emmitte, K. A., KESSLER, R. M., Niswender, C. M., Daniels, J. S., Jones, C. K., et al. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.245 · Cited by 44 · see citing works
Self-citationDvorzhak, A., Semtner, M., Faber, D. S., & Grantyn, R. (2012) · The Journal of Physiology · doi:10.1113/jphysiol.2012.241018 · Cited by 42 · see citing works
Centonze, D., Rossi, S., Prosperetti, C., Gasperi, V., Chiara, V. D., Bari, M., Tscherter, A., Febbraro, F., Bernardi, G., & Maccarrone, M. (2007) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2007.03.005 · Cited by 32 · see citing works
Kalariya, M. V., Prajapati, R., Parmar, S. K., & Sheth, N. R. (2015) · Pharmaceutical Biology · doi:10.3109/13880209.2015.1014923 · Cited by 29 · see citing works
The Nature, Assessment, and Treatment of Obsessive–Compulsive Disorder
Mcguire, J. F., Lewin, A. B., Horng, B., Murphy, T. K., & Storch, E. A. (2012) · Postgraduate Medicine · doi:10.3810/pgm.2012.01.2528 · Cited by 28 · see citing works
Effects of mood stabilizers on marble-burying behavior in mice
Egashira, N., Abe, M., Shirakawa, A., Niki, T., Mishima, K., Iwasaki, K., Oishi, R., & Fujiwara, M. (2012) · Psychopharmacology · doi:10.1007/s00213-012-2904-9 · Cited by 25 · see citing works
The potent inhibitory effect of tipepidine on marble-burying behavior in mice
Honda, S., Kawaura, K., Soeda, F., Shirasaki, T., & Takahama, K. (2010) · Behavioural Brain Research · doi:10.1016/j.bbr.2010.08.010 · Cited by 20 · see citing works
Picconi, B., & Calabresi, P. (2014) · Movement Disorders · doi:10.1002/mds.25851 · Cited by 18 · see citing works
Functional and ultrastructural analysis of group I mGluR in striatal fast‐spiking interneurons
Bonsi, P., Sciamanna, G., Mitrano, D. A., Cuomo, D., Bernardi, G., Platania, P., Smith, Y., & Pisani, A. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05383.x · Cited by 16 · see citing works
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Foster, D. J., & Conn, P. J. (2017) · Neuron · doi:10.1016/j.neuron.2017.03.016 · Cited by 227 · see citing works
Self-citationGenetics of glutamate and its receptors in autism spectrum disorder
Nisar, S., Bhat, A. A., Masoodi, T., Hashem, S., Akhtar, S., Ali, T. A., Amjad, S., Chawla, S., Bagga, P., Frenneaux, M. P., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01506-w · Cited by 172 · see citing works
Neural Mechanisms Underlying Repetitive Behaviors in Rodent Models of Autism Spectrum Disorders
Gandhi, T., & Lee, C. C. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.592710 · Cited by 94 · see citing works
Katz, M., Corson, F., Keil, W. W., Singhal, A., Bae, A. J., Lu, Y., Liang, Y., & Shaham, S. (2019) · Nature Communications · doi:10.1038/s41467-019-09581-4 · Cited by 81 · see citing works
Strengthened Inputs from Secondary Motor Cortex to Striatum in a Mouse Model of Compulsive Behavior
Corbit, V. L., Manning, E. E., Gittis, A. H., & Ahmari, S. E. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.1728-18.2018 · Cited by 80 · see citing works
“Sapap3-KOs demonstrate ex vivo abnormalities in striatal spiny projection neurons (SPNs), including both increased NMDAreceptor mediated and reduced AMPA-receptor mediated transmission in dorsal striatum (Welch et al., 2007; Wan et al., 2011, 2014; Ade et al., 2016).”
BackgroundManning, E. E., Dombrovski, A. Y., Torregrossa, M. M., & Ahmari, S. E. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-018-0307-2 · Cited by 79 · see citing works
Automated classification of self-grooming in mice using open-source software
van den Boom, B. J. G., Pavlidi, P., Wolf, C. J. H., Mooij, A. H., & Willuhn, I. (2017) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2017.05.026 · Cited by 62 · see citing works
Gregory, K. J., & Goudet, C. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.019133 · Cited by 64 · see citing works
Shonesy, B. C., Parrish, W. P., Haddad, H. K., Stephenson, J. R., Báldi, R., Bluett, R. J., Marks, C. R., Centanni, S. W., Folkes, O. M., Spiess, K., et al. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.11.036 · Cited by 48 · see citing works
Bockaert, J., Perroy, J., & Ango, F. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.0026-21.2021 · Cited by 52 · see citing works
Esterlis, I., Holmes, S. E., Sharma, P., Krystal, J. H., & DeLorenzo, C. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.08.025 · Cited by 50 · see citing works
Ramírez-Armenta, K. I., Alatriste-León, H., Verma-Rodríguez, A. K., Llanos-Moreno, A., Ramírez‐Jarquín, J. O., & Tecuapetla, F. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-021-01161-9 · Cited by 48 · see citing works
Lamothe, H., Schreiweis, C., Mondragón-González, S. L., Rebbah, S., Lavielle, O., Mallet, L., & Burguière, E. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02323-7 · Cited by 49 · see citing works
Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice
Hadjas, L. C., Schartner, M. M., Cand, J., Creed, M. C., Pascoli, V., Lüscher, C., & Simmler, L. D. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-0747-3 · Cited by 46 · see citing works
Simmler, L. D., & Ozawa, T. (2019) · Neurochemistry International · doi:10.1016/j.neuint.2019.104464 · Cited by 40 · see citing works
Reinforcement learning detuned in addiction: integrative and translational approaches
Groman, S. M., Thompson, S. L., Lee, D., & Taylor, J. R. (2021) · Trends in Neurosciences · doi:10.1016/j.tins.2021.11.007 · Cited by 43 · see citing works
Metabotropic glutamate receptors as targets for novel anxiolytics
Ferraguti, F. (2018) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2018.02.004 · Cited by 41 · see citing works
Midbrain dopamine neurons arbiter OCD-like behavior
Xue, J., Qian, D., Zhang, B., Yang, J., Li, W., Bao, Y., Qiu, S., Fu, Y., Wang, S., Yuan, T.-F., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2207545119 · Cited by 40 · see citing works
Hyperactivity of indirect pathway-projecting spiny projection neurons promotes compulsive behavior
Piantadosi, S. C., Manning, E. E., Chamberlain, B. L., Hyde, J., LaPalombara, Z., Bannon, N. M., Pierson, J. L., Namboodiri, V. M. K., & Ahmari, S. E. (2024) · Nature Communications · doi:10.1038/s41467-024-48331-z · Cited by 39 · see citing works
Manning, E. E., Wang, A. Y., Saikali, L. M., Winner, A. S., & Ahmari, S. E. (2021) · Scientific Reports · doi:10.1038/s41598-021-88769-5 · Cited by 36 · see citing works
Neuronal Glutamate Transporters Control Dopaminergic Signaling and Compulsive Behaviors
Bellini, S., Fleming, K. E., De, M., McCauley, J., Petroccione, M. A., D’Brant, L. Y., Tkachenko, A., Kwon, S., Jones, L. A., & Scimemi, A. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.1906-17.2017 · Cited by 42 · see citing works
Xu, J., Marshall, J. J., Kraniotis, S., Nomura, T., Zhu, Y., & Contractor, A. (2021) · Behavioural Brain Research · doi:10.1016/j.bbr.2021.113378 · Cited by 34 · see citing works
Quanico, J. P., Franck, J., Wisztorski, M., Salzet, M., & Fournier, I. (2017) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2017.03.006 · Cited by 29 · see citing works
Manning, E. E., Geramita, M. A., Piantadosi, S. C., Pierson, J. L., & Ahmari, S. E. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.11.018 · Cited by 27 · see citing works
Longo, F., Aryal, S., Anastasiades, P. G., Maltese, M., Baimel, C., Albanese, F., Tabor, J., Zhu, J. D., Oliveira, M. M., Gastaldo, D., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112901 · Cited by 25 · see citing works
SAPAP Scaffold Proteins: From Synaptic Function to Neuropsychiatric Disorders
Bai, Y., Wang, H., & Li, C. (2022) · Cells · doi:10.3390/cells11233815 · Cited by 24 · see citing works
mGlu5 function in the nucleus accumbens core during the incubation of methamphetamine craving
Murray, C. H., Christian, D., Milovanovic, M., Loweth, J. A., Hwang, E.-K., Caccamise, A. J., Funke, J. R., & Wolf, M. E. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108452 · Cited by 23 · see citing works
Aubrecht, T. G., Faden, A. I., Sabirzhanov, B. E., Glaser, E. P., Roelofs, B. A., Polster, B. M., Makarevich, O. D., & Stoica, B. A. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-1156-y · Cited by 22 · see citing works
The Neuronal Glutamate Transporter EAAT3 in Obsessive-Compulsive Disorder
Escobar, A. P., Wendland, J., Chávez, A. E., & Moya, P. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01362 · Cited by 19 · see citing works
Ramos-Prats, A., Kölldorfer, J., Paolo, E., Zeidler, M., Schmid, G., & Ferraguti, F. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00030 · Cited by 21 · see citing works
Cognitive impairment and autistic-like behaviour in SAPAP4-deficient mice
Schob, C., Morellini, F., Ohana, O., Bakota, L., Hrynchak, M. V., Brandt, R., Brockmann, M. D., Cichon, N. B., Hartung, H., Hanganu‐Opatz, I. L., et al. (2019) · Translational Psychiatry · doi:10.1038/s41398-018-0327-z · Cited by 21 · see citing works
Glorie, D., Verhaeghe, J. A. J., Miranda, A., Lombaerde, S. D., Stroobants, S. G., & Staelens, S. G. (2020) · EJNMMI Research · doi:10.1186/s13550-020-00721-2 · Cited by 20 · see citing works
Shi, Y., Wang, M., Xiao, L., Gui, L., Zheng, W., Bai, L., Su, B., Li, B., Xu, Y., Pan, W. D., et al. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.1057887 · Cited by 18 · see citing works
Malgady, J. M., Baez, A., Hobel, Z. B., Jimenez, K., Goldfried, J., Prager, E. M., Wilking, J. A., Zhang, Q., Feng, G., & Plotkin, J. L. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113384 · Cited by 18 · see citing works
Zhan, Y., Xia, J., & Wang, X. (2019) · International Journal of Neuroscience · doi:10.1080/00207454.2019.1684276 · Cited by 18 · see citing works
Abe, Y., Takata, N., Sakai, Y., Hamada, H. T., Hiraoka, Y., Aida, T., Tanaka, K., Bihan, D. L., Doya, K., & Tanaka, K. F. (2020) · NeuroImage · doi:10.1016/j.neuroimage.2020.117318 · Cited by 17 · see citing works
Morris, C. W., Watkins, D. S., Salek, A. B., Edler, M., & Baucum, A. J. (2018) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2018.06.001 · Cited by 17 · see citing works
Marks, C. R., Shonesy, B. C., Wang, X., Stephenson, J. R., Niswender, C. M., & Colbran, R. J. (2018) · Molecular Pharmacology · doi:10.1124/mol.118.113142 · Cited by 16 · see citing works
Psilocybin reduces grooming in the SAPAP3 knockout mouse model of compulsive behaviour
Gattuso, J. J., Wilson, C., Hannan, A. J., & Renoir, T. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110202 · Cited by 16 · see citing works
Cao, X., Liu, W., Cheng, L., Li, H., Wu, H., Yan-hu, L., Chen, C., Xiao, X., Li, M., Wang, G., et al. (2020) · 中国科学通报：英文版 · doi:10.1016/j.scib.2020.09.021 · Cited by 14 · see citing works
Astroglia and Obsessive Compulsive Disorder
Tanaka, K. (2021) · Advances in neurobiology · doi:10.1007/978-3-030-77375-5_7 · Cited by 14 · see citing works
Gattuso, J. J., Wilson, C., Hannan, A. J., & Renoir, T. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109689 · Cited by 14 · see citing works
Hoffman, K. L., & Cano-Ramírez, H. (2017) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2018.1417379 · Cited by 14 · see citing works
Kos, J. A., Langiu, M., Hellyer, S. D., & Gregory, K. J. (2024) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.4c00213 · Cited by 12 · see citing works
Morris, C. W., Watkins, D. S., Shah, N. R., Pennington, T., Hens, B., Qi, G. D., Doud, E. H., Mosley, A. L., Atwood, B. K., & Baucum, A. J. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2022.12.008 · Cited by 11 · see citing works
Glorie, D., Verhaeghe, J. A. J., Miranda, A., Kertész, I., Wyffels, L., Stroobants, S. G., & Staelens, S. G. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108160 · Cited by 12 · see citing works
Matrisciano, F., Locci, V., Dong, E., Nicoletti, F., Guidotti, A., & Grayson, D. R. (2022) · Current Neuropharmacology · doi:10.2174/1567202619999220209112609 · Cited by 9 · see citing works
Servaes, S., Kara, F., Glorie, D., Stroobants, S. G., der Linden, A. V., & Staelens, S. G. (2018) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.118.252635 · Cited by 9 · see citing works
The metabotropic glutamate receptor 5 as a biomarker for psychiatric disorders
(2023) · International Review of Neurobiology · doi:10.1016/bs.irn.2022.10.007 · Cited by 8 · see citing works
The genetics of trichotillomania and excoriation disorder: A systematic review
Reid, M., Lin, A., Farhat, L. C., Fernandez, T. V., & Olfson, E. (2024) · Comprehensive Psychiatry · doi:10.1016/j.comppsych.2024.152506 · Cited by 11 · see citing works
Stefanik, M. T., Sakas, C., Lee, D. M., & Wolf, M. E. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.05.032 · Cited by 8 · see citing works
Analysis of Rodent Grooming and Its Microstructure in Modern Neurobiological Studies
Apukhtin, K. V., Shevlyakov, A. D., Kotova, M. M., Amikishiev, S. V., Riga, V. D., Volgin, A. D., & Kalueff, A. V. (2024) · Journal of Evolutionary Biochemistry and Physiology · doi:10.1134/s0022093024030219 · Cited by 7 · see citing works
Manning, E. E., & Ahmari, S. E. (2018) · Brain and Neuroscience Advances · doi:10.1177/2398212818783896 · Cited by 7 · see citing works
Manning, E. E., Wang, A. Y., Saikali, L. M., Winner, A. S., & Ahmari, S. E. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/694935 · Cited by 7 · see citing works
Sex and gender differences in OCD: A scoping review and a two subtypes hypothesisPreprint
Zandt, M. A. V., Olfson, E., Stahnke, B., Taylor, S., Wise, A., Williams, C., Bloch, M. H., Pittenger, C., & Pushkarskaya, H. (2025) · medRxiv · doi:10.1101/2025.02.08.25321933 · Cited by 6 · see citing works
Late development of OCD-like phenotypes in Dlgap1 knockout mice
Minagawa, K., Hayakawa, T., Akimoto, H., Nagashima, T., Takahashi, Y., & Asai, S. (2024) · Psychopharmacology · doi:10.1007/s00213-024-06668-9 · Cited by 6 · see citing works
Glorie, D., Verhaeghe, J. A. J., Miranda, A., Lombaerde, S. D., Stroobants, S. G., & Staelens, S. G. (2021) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2021.11.010 · Cited by 4 · see citing works
Meringolo, M., Montanari, M., D’Antoni, S., Martella, G., Atiallah, I. E., Ponterio, G., Tassone, A., Reverte, I., Caprioli, D., Strimpakos, G., et al. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70253 · Cited by 3 · see citing works
Aaltonen, A., Tamaki, A., Ramón, A. P., Borgkvist, A., & Santini, E. (2026) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-026-06115-2 · Cited by 2 · see citing works
Gattuso, J. J., Bezcioglu, B., Wilson, C., Havaux, K., Hannan, A. J., & Renoir, T. (2025) · Psychedelics. · doi:10.61373/pp025i.0044 · Cited by 3 · see citing works
Analyses of Rodent Grooming and its Behavioral Microstructure in Modern Neurobiological Studies
Apukhtin, K. V., Shevlyakov, A. D., Kotova, M. M., Amikishiev, S. V., Riga, V. D., Volgin, A. D., & Kalueff, A. V. (2024) · Российский физиологический журнал им И М Сеченова · doi:10.31857/s0869813924060022 · Cited by 3 · see citing works
Matosin, N., & Siegel, S. J. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.08.005 · Cited by 3 · see citing works
Longo, F., Aryal, S., Anastasiades, P. G., Maltese, M., Baimel, C., Albanese, F., Tabor, J., Zhu, J. D., Oliveira, M. M., Gastaldo, D., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.12.08.519509 · Cited by 3 · see citing works
Control of Theta Oscillatory Activity Underlying Fear Expression by mGlu5 Receptors
Matulewicz, P., Ramos-Prats, A., Gómez‐Santacana, X., Llebaria, A., & Ferraguti, F. (2022) · Cells · doi:10.3390/cells11223555 · Cited by 3 · see citing works
Dutta, N., Chatterjee, M., Saha, S., Sinha, S., & Mukhopadhyay, K. (2024) · Scientific Reports · doi:10.1038/s41598-024-59290-2 · Cited by 1 · see citing works
Paget-Blanc, V., Cavaccini, A., Longaretti, A., Nava, L., Trusel, M., Rocchi, A., Pennuto, M., Marcello, E. E., Gardoni, F., Greco, B., et al. (2025) · PLoS Biology · doi:10.1371/journal.pbio.3003288 · Cited by 2 · see citing works
Malgady, J. M., Baez, A., Jimenez, K., Hobel, Z. B., Prager, E. M., Zhang, Q., Feng, G., & Plotkin, J. L. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.02.07.479446 · Cited by 1 · see citing works
The Use of Small Animal Molecular Imaging (μPET) Exemplified in a Neurobiological Pathology
Glorie, D., Servaes, S., Miranda, A., Bertoglio, D., Verhaeghe, J. A. J., & Staelens, S. G. (2020) · Springer eBooks · doi:10.1007/978-3-030-53176-8_2
Nautilus: los secretos de una antigua criatura
de Lozoya, A. V. (2001) · Quercus eBooks
(2018) · Elsevier eBooks · doi:10.1016/b978-0-12-811351-6.00026-7
Marsicano, G., & Busquets-García, A. (2018) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.732708994.793550660
Animal and Cellular Models of Pediatric Psychiatric Disorders
Drapeau, E., Harony‐Nicolas, H., & Crawley, J. N. (2017) · Oxford University Press eBooks · doi:10.1093/med/9780190681425.003.0061
The Progress of Different Pathways for Shank3 to Cause Autism Spectrum Disorder
Stephanie, L., Song, X., & Lin, Z. (2022) · Highlights in Science Engineering and Technology · doi:10.54097/hset.v2i.584
Meringolo, M., Montanari, M., D’Antoni, S., Martella, G., Atiallah, I. E., Ponterio, G., Tassone, A., Reverte, I., Caprioli, D., Strimpakos, G., et al. (2024) · Research Square · doi:10.21203/rs.3.rs-4893764/v1
(2024) · Elsevier eBooks · doi:10.1016/b978-0-443-23565-8.09996-8
Anisman, H., Hayley, S. P., & Kusnecov, A. W. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-23565-8.00001-6
Meringolo, M., Montanari, M., D’Antoni, S., Martella, G., Atiallah, I. E., Ponterio, G., Tassone, A., Reverte, I., Caprioli, D., Strimpakos, G., et al. (2025) · Research Square · doi:10.21203/rs.3.rs-4893764/v2
Glorie, D., Verhaeghe, J., Miranda, A., Lombaerde, S. D., Stroobants, S. G., & Staelens, S. G. (2020) · Figshare · doi:10.6084/m9.figshare.13237747
Liu, X., Zhou, X., Meng, R., Chen, Y., Chen, Y., Highet, B., Curtis, M. A., Hirt, B., Yu, S., Zhou, J., et al. (2026) · Clinical and Translational Discovery · doi:10.1002/ctd2.70128
Animal models of obsessive-compulsive disorder
Moya, P. R., Ardiles, N. M., Henríquez-Belmar, F., Plaza-Briceño, W., & Acevedo-Hernández, P. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-27446-6.00008-x
Neurochemistry and neurotransmitters involved in obsessive–compulsive disorder
Grant, J., & Sohl, E. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-27446-6.00004-2
Eghdami, S., Boroon, M., Keshavarz‐Akhlaghi, A., & Shalbafan, M. (2026) · Psychopharmacology · doi:10.1007/s00213-026-07155-z
Gattuso, J. J., Bezcioglu, B., Hendey, J., Payet, J. M., Phelan, Z. J., Hale, M. W., Hannan, A. J., & Renoir, T. (2026) · Molecular Psychiatry · doi:10.1038/s41380-026-03879-8
- Authors
- Ade, K. K., Wan, Y., Hamann, H. C., O’Hare, J. K., Guo, W., Quian, A., Kumar, S., Bhagat, S., Rodriguiz, R. M., Wetsel, W. C., Conn, P. J., Dzirasa, K., Huber, K. M., & Calakos, N.
- Affiliations
- Duke University (US)
- Duke Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
- Vanderbilt University (US)
- Corresponding author
- Calakos, Nicole
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 80
- Issue
- 7
- Pages
- 522-533
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC5536332
- OpenAlex
- W2385482058
- Cited by
- 84
- References
- 64
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 11 · 2023: 5 · 2022: 10 · 2021: 10 · 2020: 8 · 2019: 9 · 2018: 10 · 2017: 8 · 2016: 1
- FWCI
- 12.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH062646)
- National Institute of General Medical Sciences (T32GM007171, T32GM008441)
- National Institute of Neurological Disorders and Stroke (R01NS064577, T32NS051156, R01NS045711, R37NS031373)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083211)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- obsessive-compulsive disorder, metabotropic glutamate receptor 5, direct and indirect striatal pathways, self-grooming, anxiety-like behavior, constitutively active receptor, mGluR5 antagonist, frontostriatal circuits
- MeSH terms
- Animals, Behavior, Animal, Corpus Striatum, Glycine, Grooming, Mice, Transgenic, Nerve Tissue Proteins, Niacinamide, Obsessive-Compulsive Disorder, Pyridines, Thiazoles, Signal Transduction, Mice, Knockout, Excitatory Amino Acid Agonists, Excitatory Amino Acid Antagonists, Mice, Receptor, Metabotropic Glutamate 5
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