{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T06:11:01Z","timestamp":1775542261204,"version":"3.50.1"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Esketamine has a significant and rapid antidepressant effect. Although studies have shown that Neuregulin 1 (NRG1) and it\u2019s signaling pathway are associated with depression, the possible regulatory relationship of esketamine on the NRG1-ErbB4 pathway is not yet clear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To induce depressive-like behavior in mice, a Chronic Social Defeat Stress (CSDS) model was established. Behavioral indicators were then employed to assess depression in these mice, categorized into control, susceptible, and resilient groups. Following intraperitoneal injection of a subanesthetic dose of esketamine, behavioral tests were conducted at 30 minutes and 24 hours post-injection to observe any improvements in depressive-like behavior. Additionally, changes in immunofluorescence and protein expression levels of NRG1-ErbB4 and GAD67 in the prefrontal cortex were evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Compared with the control group, the CSDS susceptible group mice showed decreases in social interaction ratio in the contact area, sucrose preference ratio, NRG1 immunofluorescence protein expression in the prefrontal cortex and NRG1 expression in tissue homogenate; showed significant increases in immobility time; the expression of NRG1 decreased;no significant change in GAD67 and ErbB4 expression level. in After 30 minutes of intraperitoneal injection of esketamine, the expression of NRG1 in the prefrontal cortex of susceptible mice increased significantly. no significant change in GAD67 and ErbB4 expression level. After 30 minutes and 24 hours of intraperitoneal injection of esketamine, the social interaction ratio of susceptible group improved compared to the control group, and the duration of forced swimming immobility was significantly shortened.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The subanesthetic dose of esketamine may regulate the NRG1-ErbB4 signaling pathway and improve depressive like behavior in mice.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fpsyt.2026.1722336","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T05:28:46Z","timestamp":1775539726000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Esketamine ameliorates depression-like behavior in mice via modulation of the NRG1\u2013ErbB4 pathway"],"prefix":"10.3389","volume":"17","author":[{"given":"Hang","family":"Yu","sequence":"first","affiliation":[{"name":"School of Mental Health, Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuqiong","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Mental Health, Bengbu Medical University","place":["Bengbu, Anhui, China"]},{"name":"Linping Hospital of Integrated Traditional Chinese and Western Medicine","place":["Hangzhou, Zhejiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[{"name":"Hefei University of Technology","place":["Hefei, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yifan","family":"He","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[{"name":"School of Mental Health, Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuxuan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Mental Health, Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ning","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Mental Health, Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nuo","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Mental Health, Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Mental Health, Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongtao","family":"Song","sequence":"additional","affiliation":[{"name":"School of Mental Health, Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenjuan","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Mental Health, Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2004.02.033","article-title":"Depression: a case of neuronal life and death","volume":"56","author":"Duman","year":"2004","journal-title":"Biol Psychiatry"},{"key":"B2","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1126\/science.1222939","article-title":"Synaptic dysfunction in depression: potential therapeutic targets","volume":"338","author":"Duman","year":"2012","journal-title":"Sci (New York N.Y.)"},{"key":"B3","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/s41386-023-01629-w","article-title":"Ketamine and rapid antidepressant action: New treatments and novel synaptic signaling mechanisms","volume":"49","author":"Krystal","year":"2024","journal-title":"Neuropsychopharmacology"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2017.210","article-title":"The ketamine metabolite 2R,6R-hydroxynorketamine blocks NMDA receptors and impacts downstream signaling linked to antidepressant effects","volume":"43","author":"Kavalali","year":"2018","journal-title":"Neuropsychopharmacology"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.4088\/jcp.v69n0610","article-title":"Rapid onset of antidepressant action: a new paradigm in the research and treatment of major depressive disorder","volume":"69","author":"MaChado-Vieira","year":"2008","journal-title":"J Clin Psychiatry"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2019.09.010","article-title":"Efficacy and safety of esketamine combined with oral antidepressants in adults with treatment-resistant depression: A multicenter, randomized, double-blind, placebo-controlled, proof-of-concept study","volume":"87","author":"Sanacora","year":"2020","journal-title":"Biol Psychiatry"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.smrv.2022.101654","article-title":"Esketamine for postoperative sleep disturbance: Clinical evidence, mechanisms, and future directions","volume":"68","author":"Malcolm","year":"2023","journal-title":"Sleep Med Rev"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2009.11.010","article-title":"Additive effect of NRG1 and DISC1 genes on lateral ventricle enlargement in first episode schizophrenia","volume":"53","author":"Mata","year":"2010","journal-title":"NeuroImage"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2008.11.002","article-title":"Altered growth factor signaling pathways as the basis of aberrant stem cell maturation in schizophrenia","volume":"121","author":"Kalkman","year":"2009","journal-title":"Pharmacol Ther"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2005.06.011","article-title":"Schizophrenia: genes at last","volume":"21","author":"Owen","year":"2005","journal-title":"Trends genetics: TIG"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2010.03.017","article-title":"Stimulated gene expression profiles as a blood marker of major depressive disorder","volume":"68","author":"Spijker","year":"2010","journal-title":"Biol Psychiatry"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1017\/neu.2017.37","article-title":"BDNF and NRG1 polymorphisms and temperament in selective serotonin reuptake inhibitor-treated patients with major depression","volume":"30","author":"Andre","year":"2018","journal-title":"Acta neuropsychiatrica"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.081071198","article-title":"Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia","volume":"98","author":"Hakak","year":"2001","journal-title":"Proc Natl Acad Sci United States America"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpsychires.2010.04.011","article-title":"Clinical variations modulate patterns of gene expression and define blood biomarkers in major depression","volume":"44","author":"Belzeaux","year":"2010","journal-title":"J Psychiatr Res"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e553","DOI":"10.1038\/tp.2015.47","article-title":"The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response","volume":"5","author":"Biernacka","year":"2015","journal-title":"Trans Psychiatry"},{"key":"B16","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1016\/j.biopsych.2008.09.031","article-title":"Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression","volume":"65","author":"Hajszan","year":"2009","journal-title":"Biol Psychiatry"},{"key":"B17","doi-asserted-by":"publisher","first-page":"e26610","DOI":"10.1371\/journal.pone.0026610","article-title":"Subchronic peripheral neuregulin-1 increases ventral hippocampal neurogenesis and induces antidepressant-like effects","volume":"6","author":"Mahar","year":"2011","journal-title":"PloS One"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.b.32428","article-title":"Genetic association between NRG1 and schizophrenia, major depressive disorder, bipolar disorder in Han Chinese population","author":"Wen","year":"2016","journal-title":"Am J Med Genet Part B Neuropsychiatr genetics: Off Publ Int Soc Psychiatr Genet"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2392","article-title":"Neuregulin 1 in neural development, synaptic plasticity and schizophrenia","volume":"9","author":"Mei","year":"2008","journal-title":"Nat Rev Neurosci"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.27.16643","article-title":"A common requirement for the catalytic activity and both SH2 domains of SHP-2 in mitogen-activated protein (MAP) kinase activation by the ErbB family of receptors. A specific role for SHP-2 in map, but not c-Jun amino-terminal kinase activation","volume":"273","author":"Deb","year":"1998","journal-title":"J Biol Chem"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/87865","article-title":"The cellular neurobiology of depression","volume":"7","author":"Manji","year":"2001","journal-title":"Nat Med"},{"key":"B22","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.bbi.2022.12.019","article-title":"Microglia-dependent excessive synaptic pruning leads to cortical underconnectivity and behavioral abnormality following chronic social defeat stress in mice","volume":"109","author":"Wang","year":"2023","journal-title":"Brain behavior Immun"},{"key":"B23","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/j.biopsych.2007.02.006","article-title":"Chronic unpredictable stress decreases cell proliferation in the cerebral cortex of the adult rat","volume":"62","author":"Banasr","year":"2007","journal-title":"Biol Psychiatry"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.01.009","article-title":"Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and Malignant glioma","volume":"53","author":"Ligon","year":"2007","journal-title":"Neuron"},{"key":"B25","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/nn.3275","article-title":"Allele-specific FKBP5 DNA demethylation mediates gene\u2013childhood trauma interactions","volume":"16","author":"Klengel","year":"2013","journal-title":"Nat Neurosci"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1010669107","article-title":"ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation","volume":"107","author":"Chen","year":"2010","journal-title":"Proc Natl Acad Sci United States America"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/s00221-019-05680-2","article-title":"NRG1-ErbB4 signaling promotes functional recovery in a murine model of traumatic brain injury via regulation of GABA release","volume":"237","author":"Deng","year":"2019","journal-title":"Exp Brain Res"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.neuroscience.2014.01.065","article-title":"Acute ketamine produces antidepressant effects through the activation of mammalian target of rapamycin (mTOR) signaling pathway and NRG1-ErbB4 pathway in the rat hippocampus","volume":"266","author":"Wang","year":"2014","journal-title":"Neuroscience"},{"key":"B29","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1038\/s41398-021-01255-4","article-title":"Neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamine","volume":"11","author":"Grieco","year":"2021","journal-title":"Transl Psychiatry"},{"key":"B30","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1038\/nprot0415-644a","article-title":"Corrigendum: a standardized protocol for repeated social defeat stress in mice","volume":"10","author":"Golden","year":"2015","journal-title":"Nat Protoc"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.yhbeh.2006.06.022","article-title":"Social conflict models: can they inform us about human psychopathology","volume":"50","author":"Huhman","year":"2006","journal-title":"Hormones Behav"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/nn1659","article-title":"Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action","volume":"9","author":"Tsankova","year":"2006","journal-title":"Nat Neurosci"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0002-1","article-title":"Stimulation of entorhinal cortex-dentate gyrus circuitry is antidepressive","volume":"24","author":"Yun","year":"2018","journal-title":"Nat Med"},{"key":"B34","first-page":"499","article-title":"Comorbidity of anxiety and depressive disorders: a helplessness-hopelessness perspective","volume-title":"Comorbidity of Mood and Anxiety Disorders","author":"Alloy","year":"1990"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/s11689-009-9017-8","article-title":"Deficient NRG1-ERBB signaling alters social approach: relevance to genetic mouse models of schizophrenia","volume":"1","author":"Moy","year":"2009","journal-title":"J Neurodev Disord"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.26402\/jpp.2024.6.01","article-title":"The role of the neuregulin 1-ErbB4 signaling pathway in neurological disorders","volume":"75","author":"Ding","year":"2024","journal-title":"J Physiol Pharmacol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-023-03278-y","article-title":"Dysfunction of NRG1\/ErbB4 signaling in the hippocampus might mediate long-term memory decline after systemic inflammation","volume":"60","author":"Gao","year":"2023","journal-title":"Mol Neurobiol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2568-10.2011","article-title":"Axonally derived neuregulin-1 is required for remyelination and regeneration after nerve injury in adulthood","volume":"31","author":"Fricker","year":"2011","journal-title":"J Neurosci"},{"key":"B39","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1038\/s41398-020-00935-x","article-title":"Nedd4l downregulation of NRG1 in the mPFC induces depression-like behaviour in CSDS mice","volume":"10","author":"Xu","year":"2020","journal-title":"Trans Psychiatry"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1017\/s1461145709990587","article-title":"Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression","volume":"13","author":"Karolewicz","year":"2010","journal-title":"Int J Neuropsychopharmacol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1503\/jpn.100048","article-title":"trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders","volume":"36","author":"Thompson Ray","year":"2011","journal-title":"J Psychiatry Neurosci"},{"key":"B42","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/j.biopsych.2021.10.022","article-title":"Deficiency of glycosylated \u03b1-dystroglycan in ventral hippocampus bridges the destabilization of gamma-aminobutyric acid type A receptors with the depressive-like behaviors of male mice","volume":"91","author":"Xie","year":"2022","journal-title":"Biol Psychiatry"},{"key":"B43","doi-asserted-by":"publisher","first-page":"2470547017720459","DOI":"10.1177\/2470547017720459","article-title":"Characterization of GABAergic marker expression in the chronic unpredictable stress model of depression","volume":"1","author":"Banasr","year":"2017","journal-title":"Chronic Stress (Thousand Oaks)"},{"key":"B44","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.neuroscience.2010.01.022","article-title":"Organization of NMDA receptors at extrasynaptic locations","volume":"167","author":"Petralia","year":"2010","journal-title":"Neuroscience"},{"key":"B45","doi-asserted-by":"publisher","first-page":"e632","DOI":"10.1038\/tp.2015.136","article-title":"R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects","volume":"5","author":"Yang","year":"2015","journal-title":"Transl Psychiatry"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2911","article-title":"Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders","volume":"11","author":"Hardingham","year":"2010","journal-title":"Nat Rev Neurosci"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhj003","article-title":"Frontostriatal microstructure modulates efficient recruitment of cognitive control","volume":"16","author":"Liston","year":"2005","journal-title":"Cereb Cortex"},{"key":"B48","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1038\/s41467-019-13809-8","article-title":"Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines","volume":"11","author":"Ali","year":"2020","journal-title":"Nat Commun"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2011.05.035","article-title":"Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression","volume":"224","author":"Koike","year":"2011","journal-title":"Behav Brain Res"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1007\/s10787-022-01031-w","article-title":"Role of the NRG1\/ErbB4 and PI3K\/AKT\/mTOR signaling pathways in the anti-psychotic effects of aripiprazole and sertindole in ketamine-induced schizophrenia-like behaviors in rats","volume":"30","author":"Nawwar","year":"2022","journal-title":"Inflammopharmacology"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01137-7","article-title":"The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons","volume":"28","author":"Wang","year":"2023","journal-title":"Mol Psychiatry"},{"key":"B52","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.neuron.2014.06.007","article-title":"Neuregulin-ERBB signaling in the nervous system and neuropsychiatric diseases","volume":"83","author":"Mei","year":"2014","journal-title":"Neuron"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2019.00087","article-title":"Cortical GABAergic dysfunction in stress and depression: new insights for therapeutic interventions","volume":"13","author":"Foga\u00e7a","year":"2019","journal-title":"Front Cell Neurosci"}],"container-title":["Frontiers in Psychiatry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2026.1722336\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T05:28:48Z","timestamp":1775539728000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2026.1722336\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,7]]},"references-count":53,"alternative-id":["10.3389\/fpsyt.2026.1722336"],"URL":"https:\/\/doi.org\/10.3389\/fpsyt.2026.1722336","relation":{},"ISSN":["1664-0640"],"issn-type":[{"value":"1664-0640","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,7]]},"article-number":"1722336"}}