Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility
Open accessAbstract
Significance: Although mutations in the neuroligin-3 and neuroligin-4 genes are implicated in autism syndromes, very little is known about the contribution of neuroligin-2 to neuropsychiatric disease states. We report a decrease in neuroligin-2 gene expression in the postmortem nucleus accumbens (NAc) of depressed patients. Reverse translation of this finding in chronic social defeat stress, an animal model of depression that enables investigation of both susceptibility and resiliency mechanisms, uncovers an important functional role for NAc neuroligin-2 in stress susceptibility. We detail a cell-type-specific role for NAc neuroligin-2 in modulating social avoidance behavior and dominance behaviors important for resiliency. Together, these findings describe a role for NAc neuroligin-2 in depression and chronic stress behaviors.
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Nlgn2 is decreased specifically in D1-MSNs of susceptible mice.
“Synaptic cell-adhesion molecule Neurologin 2 (Nlgn2) is decreased specifically in D1-MSNs of susceptible mice.”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [137]
D1-MSN Nlgn2 knockdown leads to susceptibility.
“D1-MSN Nlgn2 knockdown leads to susceptibility, whereas Nlgn2 knockdown in D2-MSNs confers resilience [137].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [137]
Nlgn2 knockdown in D2-MSNs confers resilience.
“D1-MSN Nlgn2 knockdown leads to susceptibility, whereas Nlgn2 knockdown in D2-MSNs confers resilience [137].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [137]
Cites
Krishnan, V., Han, M.-H., Graham, D. L., Berton, O., Renthal, W., Russo, S. J., LaPlant, Q., Graham, A., Lutter, M., Lagace, D. C., et al. (2007) · Cell · doi:10.1016/j.cell.2007.09.018 · Cited by 2,307 · see citing works
Self-citationEssential role of BDNF in the mesolimbic dopamine pathway in social defeat stress
Berton, O., McClung, C. A., DiLeone, R. J., Krishnan, V., Renthal, W., Russo, S. J., Graham, D., Tsankova, N. M., Bolanos, C. A., Rios, M., et al. (2006) · Science · doi:10.1126/science.1120972 · Cited by 2,129 · see citing works
Self-citationThe brain reward circuitry in mood disorders
Russo, S. J., & Nestler, E. J. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3381 · Cited by 1,870 · see citing works
Self-citationMutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism
Study, P. A. R. I. S., Jamain, S., Quach, H., Betancur, C., Råstam, M., Colineaux, C., Gillberg, I. C., Soderstrom, H., Giros, B., Leboyer, M., et al. (2003) · Nature Genetics · doi:10.1038/ng1136 · Cited by 1,851 · see citing works
Neuroligins and neurexins link synaptic function to cognitive disease
Südhof, T. C. (2008) · Nature · doi:10.1038/nature07456 · Cited by 1,849 · cited 6× · see citing works
“The NLGN family has been heavily implicated in the etiology of social neuropsychiatric disorders such as autism and schizophrenia (14, 15), and more recently, a case report identified a nonsense mutation of NLGN-2 as possibly underlying anxiety behavior (11).”
BackgroundInfluentialA standardized protocol for repeated social defeat stress in mice
Golden, S. A., Covington, H. E., Berton, O., & Russo, S. J. (2011) · Nature Protocols · doi:10.1038/nprot.2011.361 · Cited by 1,581 · see citing works
Self-citationStress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex
McEwen, B. S., Nasca, C., & Gray, J. D. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.171 · Cited by 1,574 · see citing works
Psychobiology and molecular genetics of resilience
Feder, A., Nestler, E. J., & Charney, D. S. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2649 · Cited by 1,272 · see citing works
Russo, S. J., Murrough, J. W., Han, M.-H., Charney, D. S., & Nestler, E. J. (2012) · Nature Neuroscience · doi:10.1038/nn.3234 · Cited by 1,206 · see citing works
Self-citationThe Psychobiology of Depression and Resilience to Stress: Implications for Prevention and Treatment
Southwick, S. M., Vythilingam, M., & Charney, D. S. (2005) · Annual Review of Clinical Psychology · doi:10.1146/annurev.clinpsy.1.102803.143948 · Cited by 1,160 · see citing works
Neuroligin Expressed in Nonneuronal Cells Triggers Presynaptic Development in Contacting Axons
Scheiffele, P., Fan, J., Choih, J., Fetter, R., & Serafini, T. (2000) · Cell · doi:10.1016/s0092-8674(00)80877-6 · Cited by 1,060 · see citing works
Neuroligins Determine Synapse Maturation and Function
Varoqueaux, F., Aramuni, G., Rawson, R. L., Mohrmann, R., Missler, M., Gottmann, K., Zhang, W., Südhof, T. C., & Brose, N. (2006) · Neuron · doi:10.1016/j.neuron.2006.09.003 · Cited by 818 · see citing works
Coping styles and behavioural flexibility: towards underlying mechanisms
Coppens, C. M., de Boer, S. F., & Koolhaas, J. M. (2010) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2010.0217 · Cited by 610 · see citing works
Chubykin, A. A., Atasoy, D., Etherton, M. R., Brose, N., Kavalali, E. T., Gibson, J. R., & Südhof, T. C. (2007) · Neuron · doi:10.1016/j.neuron.2007.05.029 · Cited by 594 · see citing works
Neuroligin 2 is exclusively localized to inhibitory synapses
Varoqueaux, F., Jamain, S., & Brose, N. (2004) · European Journal of Cell Biology · doi:10.1078/0171-9335-00410 · Cited by 552 · see citing works
Bidirectional control of social hierarchy by synaptic efficacy in medial prefrontal cortex
Wang, F., Zhu, J., Zhu, H., Zhang, Q., Lin, Z., & Hu, H. (2011) · Science · doi:10.1126/science.1209951 · Cited by 528 · see citing works
Rothwell, P. E., Fuccillo, M. V., Maxeiner, S., Hayton, S. J., Gokce, O., Lim, B. K., Fowler, S. C., Malenka, R. C., & Südhof, T. C. (2014) · Cell · doi:10.1016/j.cell.2014.04.045 · Cited by 477 · see citing works
Aggressive behavioral phenotypes in mice
Miczek, K. A., Maxson, S. C., Fish, E. W., & Faccidomo, S. (2001) · Behavioural Brain Research · doi:10.1016/s0166-4328(01)00298-4 · Cited by 448 · see citing works
Francis, T. C., Chandra, R., Friend, D. M., Finkel, E., Dayrit, G., Miranda, J., Brooks, J. M., Iñiguez, S. D., O’Donnell, P., Kravitz, A., et al. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.07.021 · Cited by 379 · see citing works
Self-citationLobo, M. K., & Nestler, E. J. (2011) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2011.00041 · Cited by 371 · see citing works
Self-citationEpigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression
Golden, S. A., Christoffel, D. J., Heshmati, M., Hodes, G. E., Magida, J., Davis, K., Cahill, M. E., Dias, C., Ribeiro, E., Ables, J. L., et al. (2013) · Nature Medicine · doi:10.1038/nm.3090 · Cited by 322 · see citing works
Self-citationSocial Dominance in Inbred Mouse Strains
Lindzey, G. E., Winston, H. D., & Manosevitz, M. (1961) · Nature · doi:10.1038/191474a0 · Cited by 290 · see citing works
IκB Kinase Regulates Social Defeat Stress-Induced Synaptic and Behavioral Plasticity
Christoffel, D. J., Golden, S. A., Dumitriu, D., Robison, A. J., Janssen, W. G., Ahn, H. F., Krishnan, V., Reyes, C. M., Han, M.-H., Ables, J. L., et al. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.4763-10.2011 · Cited by 267 · see citing works
Self-citationIacoviello, B. M., & Charney, D. S. (2014) · European Journal of Psychotraumatology · doi:10.3402/ejpt.v5.23970 · Cited by 254 · see citing works
Nuclear Factor κB Signaling Regulates Neuronal Morphology and Cocaine Reward
Russo, S. J., Wilkinson, M. B., Mazei‐Robison, M. S., Dietz, D., Maze, I. S., Krishnan, V., Renthal, W. R., Graham, A., Birnbaum, S. G., Green, T. A., et al. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.6173-08.2009 · Cited by 248 · see citing works
Self-citationBasal forebrain projections to the lateral habenula modulate aggression reward
Golden, S. A., Heshmati, M., Flanigan, M. E., Christoffel, D. J., Guise, K. G., Pfau, M. L., Aleyasin, H., Ménard, C., Zhang, H., Hodes, G. E., et al. (2016) · Nature · doi:10.1038/nature18601 · Cited by 241 · see citing works
Self-citationβ-catenin mediates stress resilience through Dicer1/microRNA regulation
Dias, C., Feng, J., Sun, H., Shao, N. Y., Mazei-Robison, M. S., Damez-Werno, D., Scobie, K., Bagot, R., LaBonté, B., Ribeiro, E., et al. (2014) · Nature · doi:10.1038/nature13976 · Cited by 240 · see citing works
Blundell, J. J., Tabuchi, K., Bolliger, M. F., Blaiss, C. A., Brose, N., Liu, X., Südhof, T. C., & Powell, C. M. (2008) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2008.00455.x · Cited by 204 · see citing works
Gibson, J. R., Huber, K., & Südhof, T. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.2457-09.2009 · Cited by 181 · see citing works
Veenema, A. H., & Neumann, I. D. (2007) · Brain Behavior and Evolution · doi:10.1159/000105491 · Cited by 149 · see citing works
Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development
Pettem, K. L., Yokomaku, D., Takahashi, H., Ge, Y., & Craig, A. M. (2013) · The Journal of Cell Biology · doi:10.1083/jcb.201206028 · Cited by 145 · see citing works
Sun, C., Cheng, M.-C., Qin, R., Liao, D., Chen, T.-T., Koong, F., Chen, G., & Chen, C. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr208 · Cited by 129 · see citing works
Parente, D. J., Garriga, C., Baskin, B., Douglas, G., Cho, M. T., Araujo, G. C., & Shinawi, M. S. (2016) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.37977 · Cited by 129 · see citing works
Depression, IV: STAR*D Treatment Trial for Depression
Rush, A. J., Trivedi, M. H., & Fava, M. (2003) · American Journal of Psychiatry · doi:10.1176/appi.ajp.160.2.237 · Cited by 127 · see citing works
Uchigashima, M., Ohtsuka, T., Kobayashi, K., & Watanabe, M. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1514074113 · Cited by 126 · see citing works
Opposing Role for Egr3 in Nucleus Accumbens Cell Subtypes in Cocaine Action
Chandra, R., Francis, T. C., Konkalmatt, P. R., Amgalan, A., Gancarz, A. M., Dietz, D., & Lobo, M. K. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0548-15.2015 · Cited by 124 · see citing works
Self-citationIntermale aggression and dark/light preference in ten inbred mouse strains
Guillot, P.-V., & Chapouthier, G. (1996) · Behavioural Brain Research · doi:10.1016/0166-4328(95)00163-8 · Cited by 117 · see citing works
Liang, J., Xu, W., Hsu, Y.-T., Yee, A. X., Chen, L., & Südhof, T. C. (2015) · Molecular Psychiatry · doi:10.1038/mp.2015.31 · Cited by 110 · see citing works
Dopamine D2 Receptor Overexpression Alters Behavior and Physiology in Drd2-EGFP Mice
Kramer, P. F., Christensen, C. H., Hazelwood, L. A., Dobi, A., Bock, R., Sibley, D. R., Mateo, Y., & Alvarez, V. A. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.4287-10.2011 · Cited by 103 · see citing works
Excitatory transmission at thalamo-striatal synapses mediates susceptibility to social stress
Christoffel, D. J., Golden, S. A., Walsh, J. J., Guise, K. G., Heshmati, M., Friedman, A. K., Dey, A., Smith, M., Rebusi, N., Pfau, M., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4034 · Cited by 101 · see citing works
Self-citationWommack, J. C., & Delville, Y. (2003) · Physiology & Behavior · doi:10.1016/j.physbeh.2003.08.002 · Cited by 89 · see citing works
van der Kooij, M. A., Fantin, M., Kraev, I., Korshunova, I., Grosse, J., Zanoletti, O., Guirado, R., García-Mompó, C., Nácher, J., Stewart, M. G., et al. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.315 · Cited by 89 · see citing works
Jiang-Xie, L.-F., Liao, H., Chen, C., Chen, Y.-T., Ho, S., Lu, D., Lee, L., Liou, H., Fu, W., & Gau, S. S. (2014) · Molecular Autism · doi:10.1186/2040-2392-5-32 · Cited by 82 · see citing works
Effects of Inhibitor of κB Kinase Activity in the Nucleus Accumbens on Emotional Behavior
Christoffel, D. J., Golden, S. A., Heshmati, M., Graham, A., Birnbaum, S., Neve, R. L., Hodes, G. E., & Russo, S. J. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.121 · Cited by 78 · see citing works
Self-citationKohl, C., Wang, X.-D., Grosse, J., Fournier, C., Harbich, D., Westerholz, S., Li, J.-T., Bacq, A., Sippel, C., Hausch, F., et al. (2015) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2015.02.016 · Cited by 76 · see citing works
Laredo, S. A., Steinman, M. Q., Robles, C. F., Ferrer, E., Ragen, B. J., & Trainor, B. C. (2015) · European Journal of Neuroscience · doi:10.1111/ejn.12824 · Cited by 75 · see citing works
Khibnik, L. A., Beaumont, M., Doyle, M., Heshmati, M., Slesinger, P. A., Nestler, E. J., & Russo, S. J. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.05.022 · Cited by 67 · see citing works
Self-citationBabaev, O., Botta, P., Meyer, E., Müller, C. R., Ehrenreich, H., Brose, N., Lüthi, A., & Krueger‐Burg, D. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.06.016 · Cited by 64 · see citing works
The reinforcing value of several types of aggressive behavior: A review
Potegal, M. (1979) · Aggressive Behavior · doi:10.1002/1098-2337(1979)5:4 · Cited by 63 · see citing works
Golden, S. A., Aleyasin, H., Heins, R., Flanigan, M. E., Heshmati, M., Takahashi, A., Russo, S. J., & Shaham, Y. (2016) · Genes Brain & Behavior · doi:10.1111/gbb.12310 · Cited by 58 · see citing works
Self-citationKohl, C., Riccio, O., Grosse, J., Zanoletti, O., Fournier, C., Schmidt, M. V., & Sandi, C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056871 · Cited by 57 · see citing works
Briand, L. A., Hilário, M. R. F., Dow, H. C., Brodkin, E. S., Blendy, J. A., & Berton, O. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.4685-14.2015 · Cited by 42 · see citing works
Genetic dissection of intermale aggressive behavior in BALB/cJ and A/J mice
Dow, H. C., Kreibich, A. S., Kaercher, K. A., Sankoorikal, G. M. V., Pauley, E. D., Lohoff, F. W., Ferraro, T. N., Li, H., & Brodkin, E. S. (2010) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2010.00640.x · Cited by 30 · see citing works
Nehrenberg, D. L., Wang, S., Buus, R. J., Perkins, J., de Villena, F. P., & Pomp, D. (2010) · BMC Genetics · doi:10.1186/1471-2156-11-113 · Cited by 13 · see citing works
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The molecular and cellular mechanisms of depression: a focus on reward circuitry
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Fox, M. E., Chandra, R., Menken, M. S., Larkin, E. J., Nam, H., Engeln, M., Francis, T. C., & Lobo, M. K. (2020) · Molecular Psychiatry · doi:10.1038/s41380-018-0211-5 · Cited by 100 · see citing works
Self-citationFreire-Cobo, C., & Wang, J. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173362 · Cited by 11 · see citing works
- Authors
- Heshmati, M., Aleyasin, H., Menard, C., Christoffel, D. J., Flanigan, M. E., Pfau, M. L., Hodes, G. E., Lepack, A. E., Bicks, L. K., Takahashi, A., Chandra, R., Turecki, G., Lobo, M. K., Maze, I., Golden, S. A., & Russo, S. J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Fishberg Department of Neuroscience, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
- Stanford University (US)
- University of Tsukuba (JP)
- University of Maryland, Baltimore (US)
- Douglas Mental Health University Institute (CA)
- National Institute on Drug Abuse (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-01-16
- Volume
- 115
- Issue
- 5
- Pages
- 1111-1116
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5798379
- OpenAlex
- W2783611325
- Cited by
- 75
- References
- 54
- Citations by year
- 2026: 7 · 2025: 1 · 2024: 10 · 2023: 3 · 2022: 11 · 2021: 18 · 2020: 9 · 2019: 10 · 2018: 5
- FWCI
- 4.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Mental Health (R01MH090264, F30MH100835, T32MH087004, F31MH105217, T32MH096678)
- HHS | NIH | National Institute of General Medical Sciences (1F12GM117583-01)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- neuroligin-2, nucleus accumbens, depression, stress vulnerability, chronic social defeat stress, dopamine D1 receptor, dopamine D2 receptor, cell type-specific gene expression, behavioral coping, defensive behavior, subordination, major depressive disorder, neuropsychiatric disorders
- MeSH terms
- Aggression, Animals, Antidepressive Agents, Behavior, Animal, Cell Line, Depressive Disorder, Major, Major Depressive Disorder, Disease Models, Animal, Dominance-Subordination, Heterozygote, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Nucleus Accumbens, RNA, Messenger, Social Behavior, Stress, Psychological, Synapses, Cell Adhesion Molecules, Neuronal, Receptors, Dopamine D1, Receptors, Dopamine D2, MicroRNAs, Mice
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