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dc.contributor.authorSaunders, Justin M.
dc.contributor.authorMuguruza Millán, Carolina ORCID
dc.contributor.authorSierra, Salvador
dc.contributor.authorMoreno, José L.
dc.contributor.authorCallado Hernando, Luis Felipe ORCID
dc.contributor.authorMeana Martínez, José Javier ORCID
dc.contributor.authorBeardsley, Patrick M.
dc.contributor.authorGonzález Maeso, Javier
dc.date.accessioned2022-11-08T18:01:53Z
dc.date.available2022-11-08T18:01:53Z
dc.date.issued2022-11
dc.identifier.citationJournal of Biological Chemistry 298(11) : (2022) // Article ID 102481es_ES
dc.identifier.issn1083-351X
dc.identifier.urihttp://hdl.handle.net/10810/58283
dc.description.abstractPrenatal environmental insults increase the risk of neurodevelopmental psychiatric conditions in the offspring. Structural modifications of dendritic spines are central to brain development and plasticity. Using maternal immune activation (MIA) as a rodent model of prenatal environmental insult, previous results have reported dendritic structural deficits in the frontal cortex. However, very little is known about the molecular mechanism underlying MIA-induced synaptic structural alterations in the offspring. Using prenatal (E12.5) injection with polyinosinic-polycytidylic acid potassium salt as a mouse MIA model, we show here that upregulation of the serotonin 5-HT2A receptor (5-HT2AR) is at least in part responsible for some of the effects of prenatal insults on frontal cortex dendritic spine structure and sensorimotor gating processes. Mechanistically, we report that this upregulation of frontal cortex 5-HT2AR expression is associated with MIA-induced reduction of nuclear translocation of the glucocorticoid receptor (GR) and, consequently, a decrease in the enrichment of GR at the 5-HT2AR promoter. The translational significance of these preclinical findings is supported by data in postmortem human brain samples suggesting dysregulation of GR translocation in frontal cortex of schizophrenia subjects. We also found that repeated corticosterone administration augmented frontal cortex 5-HT2AR expression and reduced GR binding to the 5-HT2AR promoter. However, virally (adeno-associated virus) mediated augmentation of GR function reduced frontal cortex 5-HT2AR expression and improved sensorimotor gating processes via 5-HT2AR. Together, these data support a negative regulatory relationship between GR signaling and 5-HT2AR expression in the mouse frontal cortex that may carry implications for the pathophysiology underlying 5-HT2AR dysregulation in neurodevelopmental psychiatric disorders.es_ES
dc.description.sponsorshipNational Institutes of Health R01MH084894 (to J. G.-M.), R01MH111940 (to J. G.-M.), NIH-N01DA-17-8932 (to P. M. B.), NIH-N01DA-19-8949 (to P. M. B.), and F30MH116550 (to J. M. S.), and Basque Government IT1211-19 (to J. J. M.) participated in the funding of this study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.es_ES
dc.language.isoenges_ES
dc.publisherElsevieres_ES
dc.rightsinfo:eu-repo/semantics/openAccesses_ES
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/es/*
dc.subjectmaternal immune activationes_ES
dc.subjectschizophreniaes_ES
dc.subjectserotonin 5-HT2A receptores_ES
dc.subjectglucocorticoid receptores_ES
dc.subjectG protein–coupled receptores_ES
dc.subjectneurodevelopmental psychiatric conditionses_ES
dc.subjectdendritic spineses_ES
dc.titleGlucocorticoid receptor dysregulation underlies 5-HT2AR-dependent synaptic and behavioral deficits in a mouse neurodevelopmental disorder model.es_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.rights.holder© 2022 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC-BY license (http://creativecommons.org/licenses/by/4.0/).es_ES
dc.rights.holderAtribución 3.0 España*
dc.relation.publisherversionhttps://www.sciencedirect.com/science/article/pii/S0021925822009243?via%3Dihubes_ES
dc.identifier.doi10.1016/j.jbc.2022.102481
dc.departamentoesFarmacologíaes_ES
dc.departamentoeuFarmakologiaes_ES


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© 2022 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC-BY license (http://creativecommons.org/licenses/by/4.0/).
Except where otherwise noted, this item's license is described as © 2022 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC-BY license (http://creativecommons.org/licenses/by/4.0/).