Serotonin 2A receptors (5-HT2ARs) mediate the hallucinogenic effects of psychedelic drugs and are a key target of the leading class of medications used to treat psychotic disorders. These findings suggest that dysfunction of 5-HT2ARs may contribute to the symptoms of schizophrenia, a mental illness characterized by perceptual and cognitive disturbances. Indeed, numerous studies have found that 5-HT2ARs are reduced in the brains of individuals with schizophrenia. However, the mechanisms that regulate 5-HT2AR expression remain poorly understood. Here, we show that a physiologic environmental stimulus, sleep deprivation, significantly upregulates 5-HT2AR levels in the mouse frontal cortex in as little as 6–8 h (for mRNA and protein, respectively). This induction requires the activity-dependent immediate early gene transcription factor early growth response 3 (Egr3) as it does not occur in Egr3 deficient (−/−) mice. Using chromatin immunoprecipitation, we show that EGR3 protein binds to the promoter of Htr2a, the gene that encodes the 5-HT2AR, in the frontal cortex in vivo, and drives expression of in vitro reporter constructs via two EGR3 binding sites in the Htr2a promoter. These results suggest that EGR3 directly regulates Htr2a expression, and 5-HT2AR levels, in the frontal cortex in response to physiologic stimuli. Analysis of publicly available post-mortem gene expression data revealed that both EGR3 and HTR2A mRNA are reduced in the prefrontal cortex of schizophrenia patients compared to controls. Together these findings suggest a mechanism by which environmental stimuli alter levels of a brain receptor that may mediate the symptoms, and treatment, of mental illness.
This is a preview of subscription content, access via your institution
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Raote I, Bhattacharya A, Panicker MM. Serotonin 2A (5-HT2A) receptor function: ligand-dependent mechanisms and pathways. In: Chattopadhyay A (ed). Serotonin Receptors in Neurobiology: Boca Raton (FL), 2007.
Geyer MA, Vollenweider FX. Serotonin research: contributions to understanding psychoses. Trends Pharm Sci. 2008;29:445–53.
Lopez-Gimenez JF, Gonzalez-Maeso J. Hallucinogens and serotonin 5-HT2A receptor-mediated signaling pathways. Curr Top Behav Neurosci. 2018;36:45–73.
Aghajanian GK, Marek GJ. Serotonin and hallucinogens. Neuropsychopharmacol: Off Publ Am Coll Neuropsychopharmacol. 1999;21:16S–23S.
Nichols DE. Hallucinogens. Pharm Ther. 2004;101:131–81.
Halberstadt AL, Geyer MA. Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. Neuropharmacology. 2011;61:364–81.
Meltzer HY, Mills R, Revell S, Williams H, Johnson A, Bahr D, et al. Pimavanserin, a serotonin(2A) receptor inverse agonist, for the treatment of parkinson’s disease psychosis. Neuropsychopharmacol: Off Publ Am Coll Neuropsychopharmacol. 2010;35:881–92.
Meltzer HY, Huang M. In vivo actions of atypical antipsychotic drug on serotonergic and dopaminergic systems. Prog brain Res. 2008;172:177–97.
Laruelle M, Abi-Dargham A, Casanova MF, Toti R, Weinberger DR, Kleinman JE. Selective abnormalities of prefrontal serotonergic receptors in schizophrenia. A postmortem study. Arch Gen Psychiatry. 1993;50:810–8.
Reynolds GP, Rossor MN, Iversen LL. Preliminary studies of human cortical 5-HT2 receptors and their involvement in schizophrenia and neuroleptic drug action. J Neural Transm Suppl. 1983;18:273–7.
Eastwood SL, Burnet PW, Gittins R, Baker K, Harrison PJ. Expression of serotonin 5-HT(2A) receptors in the human cerebellum and alterations in schizophrenia. Synapse. 2001;42:104–14.
Gonzalez-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, Lopez-Gimenez JF, et al. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature. 2008;452:93–7.
Muguruza C, Moreno JL, Umali A, Callado LF, Meana JJ, Gonzalez-Maeso J. Dysregulated 5-HT(2A) receptor binding in postmortem frontal cortex of schizophrenic subjects. Eur Neuropsychopharmacol. 2013;23:852–64.
Selvaraj S, Arnone D, Cappai A, Howes O. Alterations in the serotonin system in schizophrenia: a systematic review and meta-analysis of postmortem and molecular imaging studies. Neurosci Biobehav Rev. 2014;45:233–45.
Rasmussen H, Frokjaer VG, Hilker RW, Madsen J, Anhoj S, Oranje B, et al. Low frontal serotonin 2A receptor binding is a state marker for schizophrenia? Eur Neuropsychopharmacol. 2016;26:1248–50.
Hurlemann R, Matusch A, Kuhn KU, Berning J, Elmenhorst D, Winz O, et al. 5-HT2A receptor density is decreased in the at-risk mental state. Psychopharmacol (Berl). 2008;195:579–90.
Dean B, Hayes W. Decreased frontal cortical serotonin2A receptors in schizophrenia. Schizophrenia Res. 1996;21:133–9.
Ngan ET, Yatham LN, Ruth TJ, Liddle PF. Decreased serotonin 2A receptor densities in neuroleptic-naive patients with schizophrenia: A PET study using [(18)F]setoperone. Am J Psychiatry. 2000;157:1016–8.
Lopez-Figueroa AL, Norton CS, Lopez-Figueroa MO, Armellini-Dodel D, Burke S, Akil H, et al. Serotonin 5-HT1A, 5-HT1B, and 5-HT2A receptor mRNA expression in subjects with major depression, bipolar disorder, and schizophrenia. Biol Psychiatry. 2004;55:225–33.
Matsumoto I, Inoue Y, Iwazaki T, Pavey G, Dean B. 5-HT2A and muscarinic receptors in schizophrenia: a postmortem study. Neurosci Lett. 2005;379:164–8.
Serretti A, Drago A, De Ronchi D. HTR2A gene variants and psychiatric disorders: a review of current literature and selection of SNPs for future studies. Curr Med Chem. 2007;14:2053–69.
Garbett K, Gal-Chis R, Gaszner G, Lewis DA, Mirnics K. Transcriptome alterations in the prefrontal cortex of subjects with schizophrenia who committed suicide. Neuropsychopharmacol Hung. 2008;10:9–14.
Kang K, Huang XF, Wang Q, Deng C. Decreased density of serotonin 2A receptors in the superior temporal gyrus in schizophrenia-a postmortem study. Prog Neuro-Psychopharmacol Biol Psychiatry. 2009;33:867–71.
Burnet PW, Eastwood SL, Harrison PJ. 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. Neuropsychopharmacol: Off Publ Am Coll Neuropsychopharmacol. 1996;15:442–55.
Williams AA, Ingram WM, Levine S, Resnik J, Kamel CM, Lish JR, et al. Reduced levels of serotonin 2A receptors underlie resistance of Egr3-deficient mice to locomotor suppression by clozapine. Neuropsychopharmacol: Off Publ Am Coll Neuropsychopharmacol. 2012;37:2285–98.
Thompson CL, Wisor JP, Lee CK, Pathak SD, Gerashchenko D, Smith KA, et al. Molecular and anatomical signatures of sleep deprivation in the mouse brain. Front Neurosci. 2010;4:165.
Maple AM, Zhao X, Elizalde DI, McBride AK, Gallitano AL. Htr2a expression responds rapidly to environmental stimuli in an Egr3-dependent manner. ACS Chem Neurosci. 2015;6:1137–42.
Elmenhorst D, Kroll T, Matusch A, Bauer A. Sleep deprivation increases cerebral serotonin 2A receptor binding in humans. Sleep. 2012;35:1615–23.
Tourtellotte WG, Milbrandt J. Sensory ataxia and muscle spindle agenesis in mice lacking the transcription factor Egr3. Nat Genet. 1998;20:87–91.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 2001;25:402–8.
Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2007;445:168–76.
Allen Mouse Brain Atlas. https://mouse.brain-map.org/static/atlas, Accessed 2004.
O’Donovan KJ, Baraban JM. Major Egr3 isoforms are generated via alternate translation start sites and differ in their abilities to activate transcription. Mol Cell Biol. 1999;19:4711–8.
Salotti J, Sakchaisri K, Tourtellotte WG, Johnson PF. An Arf-Egr-C/EBPbeta pathway linked to ras-induced senescence and cancer. Mol Cell Biol. 2015;35:866–83.
Grant CE, Bailey TL, Noble WS. FIMO: scanning for occurrences of a given motif. Bioinformatics. 2011;27:1017–8.
Li L, Carter J, Gao X, Whitehead J, Tourtellotte WG. The neuroplasticity-associated arc gene is a direct transcriptional target of early growth response (Egr) transcription factors. Mol Cell Biol. 2005;25:10286–300.
Edgar R, Domrachev M, Lash AE. Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30:207–10.
Lanz TA, Joshi JJ, Reinhart V, Johnson K, Grantham LE 2nd, Volfson D. STEP levels are unchanged in pre-frontal cortex and associative striatum in post-mortem human brain samples from subjects with schizophrenia, bipolar disorder and major depressive disorder. PloS ONE. 2015;10:e0121744.
Motulsky HJ, Brown RE. Detecting outliers when fitting data with nonlinear regression - a new method based on robust nonlinear regression and the false discovery rate. BMC Bioinforma. 2006;7:123.
Mengod G, Pompeiano M, Martinez-Mir MI, Palacios JM. Localization of the mRNA for the 5-HT2 receptor by in situ hybridization histochemistry. Correlation with the distribution of receptor sites. Brain Res. 1990;524:139–43.
Pompeiano M, Palacios JM, Mengod G. Distribution of the serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT2A and 5-HT2C receptors. brain Res Mol brain Res. 1994;23:163–78.
Weber ET, Andrade R. Htr2a Gene and 5-HT(2A) Receptor expression in the cerebral cortex studied using genetically modified mice. Front Neurosci. 2010;4:36.
Lopez-Rodriguez F, Wilson CL, Maidment NT, Poland RE, Engel J. Total sleep deprivation increases extracellular serotonin in the rat hippocampus. Neuroscience. 2003;121:523–30.
Van Oekelen D, Luyten WH, Leysen JE. 5-HT2A and 5-HT2C receptors and their atypical regulation properties. Life Sci. 2003;72:2429–49.
Senba E, Ueyama T. Stress-induced expression of immediate early genes in the brain and peripheral organs of the rat. Neurosci Res. 1997;29:183–207.
Murnane KS. Serotonin 2A receptors are a stress response system: implications for post-traumatic stress disorder. Behav Pharm. 2019;30:151–62.
Bekinschtein P, Renner MC, Gonzalez MC, Weisstaub N. Role of medial prefrontal cortex serotonin 2A receptors in the control of retrieval of recognition memory in rats. J Neurosci: Off J Soc Neurosci. 2013;33:15716–25.
Morici JF, Miranda M, Gallo FT, Zanoni B, Bekinschtein P, Weisstaub NV. 5-HT2a receptor in mPFC influences context-guided reconsolidation of object memory in perirhinal cortex. Elife. 2018;7:e33746.
Gallitano-Mendel A, Izumi Y, Tokuda K, Zorumski CF, Howell MP, Muglia LJ, et al. The immediate early gene early growth response gene 3 mediates adaptation to stress and novelty. Neuroscience. 2007;148:633–43.
Bhattacharyya S, Puri S, Miledi R, Panicker MM. Internalization and recycling of 5-HT2A receptors activated by serotonin and protein kinase C-mediated mechanisms. Proc Natl Acad Sci USA. 2002;99:14470–5.
Willins DL, Berry SA, Alsayegh L, Backstrom JR, Sanders-Bush E, Friedman L, et al. Clozapine and other 5-hydroxytryptamine-2A receptor antagonists alter the subcellular distribution of 5-hydroxytryptamine-2A receptors in vitro and in vivo. Neuroscience. 1999;91:599–606.
Roth BL, Palvimaki EP, Berry S, Khan N, Sachs N, Uluer A, et al. 5-Hydroxytryptamine2A (5-HT2A) receptor desensitization can occur without down-regulation. J Pharmacol Exp Ther. 1995;275:1638–46.
Akiyoshi J, Hough C, Chuang DM. Paradoxical increase of 5-hydroxytryptamine2 receptors and 5-hydroxytryptamine2 receptor mRNA in cerebellar granule cells after persistent 5-hydroxytryptamine2 receptor stimulation. Mol Pharm. 1993;43:349–55.
Falkenberg VR, Gurbaxani BM, Unger ER, Rajeevan MS. Functional genomics of serotonin receptor 2A (HTR2A): interaction of polymorphism, methylation, expression and disease association. Neuromolecular Med. 2011;13:66–76.
Carhart-Harris RL, Bolstridge M, Rucker J, Day CM, Erritzoe D, Kaelen M, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016;3:619–27.
Grob CS, Danforth AL, Chopra GS, Hagerty M, McKay CR, Halberstadt AL, et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry. 2011;68:71–8.
Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016;30:1181–97.
Nichols DE, Johnson MW, Nichols CD. Psychedelics as medicines: an emerging new paradigm. Clin Pharm Ther. 2017;101:209–19.
Meltzer HY. The role of serotonin in antipsychotic drug action. Neuropsychopharmacol: Off Publ Am Coll Neuropsychopharmacol. 1999;21:106S–115S.
Bennett JP Jr., Enna SJ, Bylund DB, Gillin JC, Wyatt RJ, Snyder SH. Neurotransmitter receptors in frontal cortex of schizophrenics. Arch Gen Psychiatry. 1979;36:927–34.
Arora RC, Meltzer HY. Serotonin2 (5-HT2) receptor binding in the frontal cortex of schizophrenic patients. J Neural Transm Gen Sect. 1991;85:19–29.
Goldman-Rakic PS. Prefrontal cortical dysfunction in schizophrenia: the relevance of working memory. Psychopathology and the Brain. 1991;6:1–23.
Berman KF, Weinberger DR. The prefrontal cortex in schizophrenia and other neuropsychiatric diseases: in vivo physiological correlates of cognitive deficits. Prog Brain Res. 1990;85:521–36.
Kupferschmidt DA, Gordon JA. The dynamics of disordered dialogue: Prefrontal, hippocampal and thalamic miscommunication underlying working memory deficits in schizophrenia. Brain Neurosci Adv. 2018;2:2398212818771821.
Laubach M, Amarante LM, Swanson K, White SR. What, if anything, is Rodent Prefrontal Cortex? eNeuro. 2018;5:ENEURO.0315-18.2018.
Sheffield JM, Barch DM. Cognition and resting-state functional connectivity in schizophrenia. Neurosci Biobehav Rev. 2016;61:108–20.
Bahner F, Meyer-Lindenberg A. Hippocampal-prefrontal connectivity as a translational phenotype for schizophrenia. Eur Neuropsychopharmacol. 2017;27:93–106.
Hu ML, Zong XF, Mann JJ, Zheng JJ, Liao YH, Li ZC, et al. A review of the functional and anatomical default mode network in Schizophrenia. Neurosci Bull. 2017;33:73–84.
Gandal MJ, Zhang P, Hadjimichael E, Walker RL, Chen C, Liu S, et al. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science. 2018;362:eaat8127.
Marballi KK, Gallitano AL. Immediate early genes anchor a biological pathway of proteins required for memory formation, long-term depression and risk for Schizophrenia. Front Behav Neurosci. 2018;12:23.
Pardinas AF, Holmans P, Pocklington AJ, Escott-Price V, Ripke S, Carrera N, et al. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat Genet. 2018;50:381–9.
Kumbrink J, Kirsch KH, Johnson JPEGR1. EGR2, and EGR3 activate the expression of their coregulator NAB2 establishing a negative feedback loop in cells of neuroectodermal and epithelial origin. J Cell Biochem. 2010;111:207–17.
Yamada K, Gerber DJ, Iwayama Y, Ohnishi T, Ohba H, Toyota T, et al. Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia. Proc Natl Acad Sci USA. 2007;104:2815–20.
Mexal S, Frank M, Berger R, Adams CE, Ross RG, Freedman R, et al. Differential modulation of gene expression in the NMDA postsynaptic density of schizophrenic and control smokers. Brain Res Mol Brain Res. 2005;139:317–32.
Kaskie RE, Graziano B, Ferrarelli F. Schizophrenia and sleep disorders: links, risks, and management challenges. Nat Sci Sleep. 2017;9:227–39.
Ferrarelli F. Sleep abnormalities in Schizophrenia: State of the Art and next steps. Am J psychiatry. 2021;178:903–13.
Yamagata K, Kaufmann WE, Lanahan A, Papapavlou M, Barnes CA, Andreasson KI, et al. Egr3/Pilot, a zinc finger transcription factor, is rapidly regulated by activity in brain neurons and colocalizes with Egr1/zif268. Learn Mem. 1994;1:140–52.
Glausier JR, Lewis DA. Dendritic spine pathology in schizophrenia. Neuroscience. 2013;251:90–107.
We are grateful to L Muppana, and D Elizalde for animal colony maintenance and technical assistance, to A. Aden, A. Barkatullah, M. Charbel, and E. Offenberg for assistance with SD studies, to Javier González-Maeso, PhD and Allan Gulledge PhD for expert advice, and to the laboratory of Stanley Watson, MD, PhD, for providing instruction and reagents for situ hybridization.
This work was supported by National Institutes of Health R01 MH097803 (ALG) and R21 MH113154-01A1 (ALG).
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Zhao, X., Ozols, A.B., Meyers, K.T. et al. Acute sleep deprivation upregulates serotonin 2A receptors in the frontal cortex of mice via the immediate early gene Egr3. Mol Psychiatry 27, 1599–1610 (2022). https://doi.org/10.1038/s41380-021-01390-w
This article is cited by