The role of reelin in the pathological mechanism of depression from clinical to rodents
Abstract
Major depressive disorder (MDD) is a devastating mental illness and the leading cause of disability worldwide. Previous studies have suggested that synaptic plasticity in the hippocampus plays an important role in depression pathogenesis. Reelin is expressed mainly in the frontal lobe and hippocampus, and is closely associated with neurodevelopment and synaptic plasticity. However, few studies have investigated its role in MDD combining clinical trials and animal experiments. We show that in a clinical trial, plasma reelin levels decreased in patients with first-episode drug-naïve MDD and increased after treatment; further, plasma reelin levels allowed to distinguish drug-naïve patients with first-episode MDD from healthy individuals. In rats, chronic mild and unpredictable stress led to a decrease in both reelin mRNA and protein levels in the hippocampus, which could be reversed by vortioxetine. Subsequent experiments confirmed that the reelin-ApoER2-NR2A /NR2B pathway regulates hippocampal synaptic plasticity and may be involved in depression or antidepressant responses. Our work contributes to a deeper understanding of MDD pathogenesis and provides new evidence that reelin should be considered a potential therapeutic target for MDD.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Behavioral studies indicate that Vortioxetine has antipsychotic and antidepressant activity in different animal models.
“Behavioral studies indicate that Vortioxetine has antipsychotic and antidepressant activity in different animal models.12”
Cites
Trivedi, M. H., Rush, A. J., Wisniewski, S. R., Nierenberg, A. A., Warden, D., Ritz, L., Norquist, G., Howland, R. H., Lebowitz, B., McGrath, P. J., et al. (2006) · American Journal of Psychiatry · doi:10.1176/appi.ajp.163.1.28 · Cited by 3,879 · see citing works
Cipriani, A., Furukawa, T. A., Salanti, G., Chaimani, A., Atkinson, L. Z., Ogawa, Y., Leucht, S., Ruhe, H. G., Turner, E. H., Higgins, J. P. T., et al. (2018) · The Lancet · doi:10.1016/s0140-6736(17)32802-7 · Cited by 3,541 · see citing works
Monyer, H., Burnashev, N., Laurie, D. J., Sakmann, B., & Seeburg, P. H. (1994) · Neuron · doi:10.1016/0896-6273(94)90210-0 · Cited by 2,989 · see citing works
Hippocampal atrophy in recurrent major depression
Sheline, Y. I., Wang, P. W., Gado, M. H., Csernansky, J. G., & Vannier, M. W. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.9.3908 · Cited by 1,932 · see citing works
Guidotti, A., Auta, J., Davis, J. M., Gerevini, V. D. G., Dwivedi, Y., Grayson, D. R., Impagnatiello, F., Pandey, G. N., Pesold, C., Sharma, R. P., et al. (2000) · Archives of General Psychiatry · doi:10.1001/archpsyc.57.11.1061 · Cited by 1,203 · see citing works
Course of illness, hippocampal function, and hippocampal volume in major depression
MacQueen, G. M., Campbell, S., McEwen, B. S., Macdonald, K., Amano, S., Joffe, R. T., Nahmias, C., & Young, L. T. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0337481100 · Cited by 980 · see citing works
MacQueen, G., & Frodl, T. (2011) · Molecular Psychiatry · doi:10.1038/mp.2010.80 · Cited by 665 · see citing works
Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning
Weeber, E. J., Beffert, U., Jones, C., Christian, J. M., Förster, E., Sweatt, J. D., & Herz, J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205147200 · Cited by 623 · see citing works
Wang, J.-W., David, D. J., Monckton, J. E., Battaglia, F., & Hen, R. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3632-07.2008 · Cited by 550 · see citing works
Beffert, U., Weeber, E. J., Durudas, A., Qiu, S., Masiulis, I., Sweatt, J. D., Li, W.-P., Adelmann, G., Frotscher, M., Hammer, R. E., et al. (2005) · Neuron · doi:10.1016/j.neuron.2005.07.007 · Cited by 497 · see citing works
Uher, R., Payne, J. L., Pavlova, B., & Perlis, R. H. (2014) · Depression and Anxiety · doi:10.1002/da.22217 · Cited by 456 · see citing works
Fatemi, S. H., Earle, J. A., & McMenomy, T. (2000) · Molecular Psychiatry · doi:10.1038/sj.mp.4000783 · Cited by 447 · see citing works
Wenzel, A., Fritschy, J., Möhler, H., & Benke, D. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.68020469.x · Cited by 442 · see citing works
Abdallah, C. G., Sanacora, G., Duman, R. S., & Krystal, J. H. (2015) · Annual Review of Medicine · doi:10.1146/annurev-med-053013-062946 · Cited by 422 · see citing works
Knable, M. B., Barci, B. M., Webster, M. J., Meador‐Woodruff, J. H., & Torrey, Ε. F. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001471 · Cited by 407 · see citing works
Pesold, C., Impagnatiello, F., Pisu, M. G., Uzunov, D. P., Costa, E., Guidotti, A., & Caruncho, H. J. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.6.3221 · Cited by 391 · see citing works
Reelin promotes hippocampal dendrite development through the VLDLR/ApoER2-Dab1 pathway
Niu, S., Renfro, A., Quattrocchi, C. C., Sheldon, M., & D'Arcangelo, G. (2004) · Neuron · doi:10.1016/s0896-6273(03)00819-5 · Cited by 375 · see citing works
Eastwood, S. L., & Harrison, P. J. (2001) · Brain Research Bulletin · doi:10.1016/s0361-9230(01)00530-5 · Cited by 262 · see citing works
Receptor compartmentalization and trafficking at glutamate synapses: a developmental proposal
van Zundert, B., Yoshii, A., & Constantine‐Paton, M. (2004) · Trends in Neurosciences · doi:10.1016/j.tins.2004.05.010 · Cited by 252 · see citing works
Vortioxetine: Clinical Pharmacokinetics and Drug Interactions
Chen, G. L., Højer, A., Areberg, J., & Nomikos, G. G. (2017) · Clinical Pharmacokinetics · doi:10.1007/s40262-017-0612-7 · Cited by 167 · see citing works
Herrera-Guzmán, I., Gudayol-Ferré, E., Herrera-Guzmán, D., Guàrdia-Olmos, J., Hinojosa-Calvo, E., & Herrera-Abarca, J. E. (2009) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2008.10.015 · Cited by 160 · see citing works
Pesold, C., Liu, W. S., Guidotti, A., Costa, E., & Caruncho, H. J. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.6.3217 · Cited by 160 · see citing works
Smalheiser, N. R., Costa, E., Guidotti, A., Impagnatiello, F., Auta, J., Lacor, P., Kriho, V., & Pappas, G. D. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.3.1281 · Cited by 158 · see citing works
Altered levels of Reelin and its isoforms in schizophrenia and mood disorders
Fatemi, S. H., Kroll, J., & Stary, J. M. (2001) · Neuroreport · doi:10.1097/00001756-200110290-00014 · Cited by 149 · see citing works
New insights into Reelin-mediated signaling pathways
Lee, G. H., & D’Arcangelo, G. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00122 · Cited by 144 · see citing works
Law, A. J., Weickert, C. S., Webster, M. J., Herman, M. M., Kleinman, J. E., & Harrison, P. J. (2003) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2003.02850.x · Cited by 141 · see citing works
Liu, W., Xue, X., Xia, J., Liu, J., & Qi, Z. (2017) · Journal of Affective Disorders · doi:10.1016/j.jad.2017.10.019 · Cited by 137 · see citing works
Iafrati, J., Orejarena, M. J., Lassalle, O., Bouamrane, L., & Chavis, P. (2014) · Molecular Psychiatry · doi:10.1038/mp.2013.66 · Cited by 132 · see citing works
Sinagra, M., Verrier, D., Frankova, D., Korwek, K. M., Blahos, J., Weeber, E. J., Manzoni, O. J., & Chavis, P. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1757-05.2005 · Cited by 128 · see citing works
Cui, Y., Cao, K., Lin, H., Cui, S., Shen, C., Wen, W., Mo, H., Dong, Z., Bai, S., Yang, L., et al. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00102 · Cited by 124 · see citing works
The neurobiology of treatment-resistant depression: A systematic review of neuroimaging studies
Runia, N., Yücel, D. E., Lok, A., de Jong, K., Denys, D. A. J. P., van Wingen, G. A., & Bergfeld, I. O. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.12.008 · Cited by 117 · see citing works
Reelin Signaling Facilitates Maturation of CA1 Glutamatergic Synapses
Qiu, S., & Weeber, E. J. (2007) · Journal of Neurophysiology · doi:10.1152/jn.00869.2006 · Cited by 115 · see citing works
Chameau, P. J. P., Inta, D., Vitalis, T., Monyer, H., Wadman, W. J., & van Hooft, J. A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810764106 · Cited by 114 · see citing works
Clarke, M., Razmjou, S., Prowse, N. A., Dwyer, Z., Litteljohn, D., Pentz, R., Anisman, H., & Hayley, S. P. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.04.021 · Cited by 94 · see citing works
Lussier, A. L., Lebedeva, K., Fenton, E. Y., Guskjolen, A., Caruncho, H., & Kalynchuk, L. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.04.012 · Cited by 88 · see citing works
Lussier, A. L., Caruncho, H. J., & Kalynchuk, L. E. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.05.050 · Cited by 84 · see citing works
Gómez-Molina, C., Sandoval, M., Henzi, R., Ramírez, J. P., Varas‐Godoy, M., Luarte, A., Lafourcade, C., Lopez‐Verrilli, M. A., Smalla, K., Kaehne, T., et al. (2018) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyy098 · Cited by 80 · see citing works
Sexually Dimorphic Changes of Hypocretin (Orexin) in Depression
Lu, J., Zhao, J., Balesar, R., Fronczek, R., Zhu, Q.-B., Wu, X.-Y., Hu, S.-H., Bao, A.-M., & Swaab, D. F. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.03.043 · Cited by 77 · see citing works
Xu, X., Xiao, X., Yan, Y., & Zhang, T. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.02.026 · Cited by 74 · see citing works
Linking peripheral IL-6, IL-1β and hypocretin-1 with cognitive impairment from major depression
Jin, K., Lü, J., Yu, Z., Shen, Z., Li, H., Mou, T., Xu, Y., & Huang, M. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.08.024 · Cited by 73 · see citing works
Self-citationReinés, A. G., Cereseto, M., Ferrero, A., Sifonios, L. L., Podestá, M. F., & Wikinski, S. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301596 · Cited by 72 · see citing works
Bosch, C., Masachs, N., Exposito-Alonso, D., Martínez, A., Teixeira, C. M., Fernaud, I., Pujadas, L., Ulloa, F., Comella, J. X., DeFelipe, J., et al. (2016) · Cerebral Cortex · doi:10.1093/cercor/bhw216 · Cited by 70 · see citing works
Soumier, A., Carter, R. M., Schoenfeld, T. J., & Cameron, H. A. (2016) · eNeuro · doi:10.1523/eneuro.0116-15.2016 · Cited by 66 · see citing works
Schwasinger-Schmidt, T. E., & Macaluso, M. (2018) · Handbook of experimental pharmacology · doi:10.1007/164_2018_167 · Cited by 63 · see citing works
Hethorn, W. R., Ciarlone, S. L., Filonova, I., Rogers, J. T., Aguirre, D., Ramirez, R. A., Grieco, J. C., Peters, M. M., Gulick, D., Anderson, A. E., et al. (2015) · European Journal of Neuroscience · doi:10.1111/ejn.12893 · Cited by 57 · see citing works
Fatemi, S. H., Reutiman, T. J., & Folsom, T. D. (2009) · Schizophrenia Research · doi:10.1016/j.schres.2009.03.002 · Cited by 55 · see citing works
Localization of apolipoprotein E receptor 2 to caveolae in the plasma membrane
Riddell, D. R., Sun, X.-M., Stannard, A. K., Soutar, A. K., & Owen, J. S. (2001) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)31625-4 · Cited by 55 · see citing works
Ignatova, N. G., Sindic, C., & Goffinet, A. M. (2004) · Neurobiology of Disease · doi:10.1016/j.nbd.2003.11.008 · Cited by 50 · see citing works
Ampuero, E., Jury, N., Härtel, S., Marzolo, M., & van Zundert, B. (2016) · Journal of Cellular Physiology · doi:10.1002/jcp.25605 · Cited by 47 · see citing works
Brymer, K. J., Johnston, J. N., Botterill, J. J., Romay-Tallón, R., Mitchell, M. A., Allen, J., Pinna, G., Caruncho, H. J., & Kalynchuk, L. E. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-0609-z · Cited by 41 · see citing works
Nonneuronal roles for the reelin signaling pathway
Khialeeva, E., & Carpenter, E. M. (2016) · Developmental Dynamics · doi:10.1002/dvdy.24462 · Cited by 40 · see citing works
Li, H., Linjuan-Li, & Wang, Y. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.09.123 · Cited by 34 · see citing works
A key requirement for synaptic Reelin signaling in ketamine-mediated behavioral and synaptic action
Kim, J., Herz, J., Kavalali, E. T., & Monteggia, L. M. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2103079118 · Cited by 28 · see citing works
Johnston, J. N., Thacker, J. S., Desjardins, C., Kulyk, B. D., Romay-Tallón, R., Kalynchuk, L. E., & Caruncho, H. J. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.559627 · Cited by 26 · see citing works
Reelin expression in brain endothelial cells: an electron microscopy study
Pérez‐Costas, E., Fenton, E. Y., & Caruncho, H. J. (2015) · BMC Neuroscience · doi:10.1186/s12868-015-0156-4 · Cited by 23 · see citing works
Reelin has antidepressant-like effects after repeated or singular peripheral injections
Allen, J., Romay-Tallón, R., Mitchell, M. A., Brymer, K. J., Johnston, J. N., Sánchez-Lafuente, C. L., Pinna, G., Kalynchuk, L. E., & Caruncho, H. J. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109043 · Cited by 22 · see citing works
Gene Expression Patterns Underlying the Reinstatement of Plasticity in the Adult Visual System
Tiraboschi, E., Guirado, R., Greco, D., Auvinen, P., Maya‐Vetencourt, J. F., Maffei, L., & Ċastrén, E. (2013) · Neural Plasticity · doi:10.1155/2013/605079 · Cited by 21 · see citing works
New Strategies for the Treatment of Neuropsychiatric Disorders Based on Reelin Dysfunction
Tsuneura, Y., NAKAI, T., Mizoguchi, H., & Yamada, K. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031829 · Cited by 19 · see citing works
Sun, Y., Li, J., Wang, L., Cong, T., Zhai, X., Li, L., Wu, H., Li, S., & Xiao, Z. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.702366 · Cited by 10 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Psychological trauma, posttraumatic stress disorder and trauma-related depression: A mini-review
Wang, S., Feng, M., Yu, F., Lv, L., Gui-lan, S., Yang, S., Guo, P., Cheng, S.-F., Qian, M., & Chen, H. (2023) · World Journal of Psychiatry · doi:10.5498/wjp.v13.i6.331 · Cited by 92 · see citing works
Chen, B., Xu, J., Chen, S., Mou, T., Wang, Y., Wang, H., Zhang, Z., Ren, F., Wang, Z., Jin, K., et al. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.01.031 · Cited by 15 · see citing works
Self-citationHalvorson, C. S., Sánchez-Lafuente, C. L., Johnston, J. N., Kalynchuk, L. E., & Caruncho, H. J. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25020814 · Cited by 16 · see citing works
Valderrama-Mantilla, A. I., Martín-Cuevas, C., Gómez-Garrido, A., Morente-Montilla, C., Crespo‐Facorro, B., & García-Cerro, S. (2025) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2025.106032 · Cited by 12 · see citing works
Sánchez-Lafuente, C. L., Martinez‐Verbo, L., Johnston, J. N., Floyd, J., Esteller, M., Kalynchuk, L. E., Ausió, J., & Caruncho, H. J. (2024) · Neuroscience Letters · doi:10.1016/j.neulet.2024.137770 · Cited by 4 · see citing works
Ye, X., Xu, P., Jiao, J., Zhao, H., Jin, K., Zhang, S., Pan, F., Chen, J., Jiang, H., Hu, J., et al. (2024) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s491768 · Cited by 3 · see citing works
Self-citationPark, D., Lee, G., Kim, B. S., Seong, M., & Kim, J. (2025) · Neuropsychopharmacology · doi:10.1038/s41386-025-02288-9 · Cited by 3 · see citing works
Reelin, the HPA Axis, and Chronic Stress: Implications for the Neurobiology of Depression
Thom, S. A., Halvorson, C. S., Reive, B. S., Sánchez-Lafuente, C. L., Kalynchuk, L. E., & Caruncho, H. J. (2026) · Chronic Stress · doi:10.1177/24705470261427267 · Cited by 3 · see citing works
Park, H. R., Cai, M., & Yang, E. J. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16091150 · Cited by 3 · see citing works
Sánchez-Lafuente, C. L., Johnston, J. N., Reive, B. S., Scheil, K., Halvorson, C. S., Jimenez, M., Colpitts, D., Kalynchuk, L. E., & Caruncho, H. J. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1442332 · Cited by 3 · see citing works
Vastrad, B. M., & Vastrad, C. M. (2025) · Egyptian Journal of Medical Human Genetics · doi:10.1186/s43042-025-00660-4 · Cited by 2 · see citing works
Halvorson, C. S., Sánchez-Lafuente, C. L., Reive, B. S., Solomons, L. S., Allen, J., Kalynchuk, L. E., & Caruncho, H. J. (2025) · Chronic Stress · doi:10.1177/24705470251381456 · Cited by 1 · see citing works
Reive, B. S., Halvorson, C., Chang, A., Allen, J., Romay-Tallón, R., Kalynchuk, L. E., & Caruncho, H. J. (2026) · Glial health research. · doi:10.1016/j.ghres.2026.100019
- Authors
- Jin, K., Zhang, S., Jiang, C., Liu, R., Chen, B., Zhao, H., Zhang, Q., Shen, Z., Xu, P., Hu, X., Jiao, J., Lu, J., & Huang, M.
- Affiliations
- First Affiliated Hospital Zhejiang University (CN)
- Zhejiang Chinese Medical University (CN)
- Children's Hospital of Zhejiang University (CN)
- Corresponding author
- Huang, Manli
- ORCID
- Venue
- Psychiatry Research
- Publisher
- Elsevier BV
- Published
- 2022-11
- Volume
- 317
- Pages
- 114838
- ISSN
- 0165-1781 (ISSN-L)
- OpenAlex
- W4294708709
- Cited by
- 13
- References
- 59
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 2
- FWCI
- 1.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Psychiatry Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81801340)
- Medical Science and Technology Project of Zhejiang Province (2022RC024)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- reelin, major depressive disorder, hippocampal synaptic plasticity, vortioxetine, ApoER2, antidepressant response, first-episode drug-naive depression, biomarkers, therapeutic target
- MeSH terms
- Reelin Protein, Animals, Clinical Trials as Topic, Depression, Depressive Disorder, Major, Major Depressive Disorder, Hippocampus, Nerve Tissue Proteins, Rodentia, Serine Endopeptidases, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review