Maternal immune activation epigenetically regulates hippocampal serotonin transporter levels
Open accessAbstract
Major depressive disorder (MDD) is one of the most debilitating psychiatric diseases, affecting a large percentage of the population worldwide. Currently, the underlying pathomechanisms remain incompletely understood, hampering the development of critically needed alternative therapeutic strategies, which further largely depends on the availability of suitable model systems. Here we used a mouse model of early life stress - a precipitating factor for the development of MDD - featuring infectious stress through maternal immune activation (MIA) by polyinosinic:polycytidilic acid (Poly(I:C)) to examine epigenetic modulations as potential molecular correlates of the alterations in brain structure, function and behavior. We found that in adult female MIA offspring anhedonic behavior was associated with modulations of the global histone acetylation profile in the hippocampus. Morevoer, specific changes at the promoter and in the expression of the serotonin transporter (SERT), critically involved in the etiology of MDD and pharmacological antidepressant treatment were detected. Furthermore, an accompanying reduction in hippocampal levels of histone deacetylase (HDAC) 1 was observed in MIA as compared to control offspring. Based on these results we propose a model in which the long-lasting impact of MIA on depression-like behavior and associated molecular and cellular aberrations in the offspring is brought about by the modulation of epigenetic processes and consequent enduring changes in gene expression. These data provide additional insights into the principles underlying the impact of early infectious stress on the development of MDD and may contribute to the development of new targets for antidepressant therapy.
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Prenatal poly(I:C) exposure alters histone acetylation of the 5-HTT promoter in hippocampus of adult mice.
“prenatal exposure to poly(I:C) alters histone acetylation of the 5-HTT promoter in the hippocampus of adult mice (Reisinger et al., 2016).”
From Neuroinflammation as a risk factor for attention deficit hyperactivity disorder (2019) · cites this paper as Reisinger et al., 2016
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Diagnostic and Statistical Manual of Mental Disorders
American Psychiatric Association (2013) · doi:10.1176/appi.books.9780890425596 · Cited by 116,369 · see citing works
Diagnostic and Statistical Manual of Mental Disorders
Williams, J. B. W., & First, M. B. (2013) · Oxford University Press eBooks · doi:10.1093/acrefore/9780199975839.013.104 · Cited by 109,841 · see citing works
Shrestha, S., & Offer, S. M. (2016) · Medical Epigenetics · doi:10.1159/000444713 · Cited by 8,949 · see citing works
Murray, C. J. L., Vos, T., Lozano, R., Naghavi, M., Flaxman, A. D., Michaud, C., Ezzati, M., Shibuya, K., Salomon, J. A., Abdalla, S., et al. (2012) · The Lancet · doi:10.1016/s0140-6736(12)61689-4 · Cited by 8,888 · see citing works
The use of the elevated plus maze as an assay of anxiety-related behavior in rodents
Walf, A. A., & Frye, C. A. (2007) · Nature Protocols · doi:10.1038/nprot.2007.44 · Cited by 3,035 · see citing works
The molecular neurobiology of depression
Krishnan, V., & Nestler, E. J. (2008) · Nature · doi:10.1038/nature07455 · Cited by 2,889 · see citing works
Cross-national epidemiology of DSM-IV major depressive episode
Bromet, E., Andrade, L. H., Hwang, I., Sampson, N. A., Alonso, J., de Girolamo, G., de Graaf, R., Demyttenaere, K., Hu, C., Iwata, N., et al. (2011) · BMC Medicine · doi:10.1186/1741-7015-9-90 · Cited by 2,221 · see citing works
Slavich, G. M., & Irwin, M. R. (2014) · Psychological Bulletin · doi:10.1037/a0035302 · Cited by 2,206 · see citing works
Sex Differences and the Epidemiology of Depression
Weissman, M. M. (1977) · Archives of General Psychiatry · doi:10.1001/archpsyc.1977.01770130100011 · Cited by 1,853 · see citing works
Functions of Site-Specific Histone Acetylation and Deacetylation
Shahbazian, M. D., & Grunstein, M. (2007) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.76.052705.162114 · Cited by 1,635 · see citing works
Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6
Smith, S. E. P., Li, J., Garbett, K., Mirnics, K., & Patterson, P. H. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.2178-07.2007 · Cited by 1,605 · see citing works
Epigenetic regulation in psychiatric disorders
Tsankova, N., Renthal, W., Kumar, A., & Nestler, E. J. (2007) · Nature reviews. Neuroscience · doi:10.1038/nrn2132 · Cited by 1,400 · see citing works
Kuehner, C. (2003) · Acta Psychiatrica Scandinavica · doi:10.1034/j.1600-0447.2003.00204.x · Cited by 839 · see citing works
Protocol for the fast chromatin immunoprecipitation (ChIP) method
Nelson, J. D., Denisenko, O. N., & Bomsztyk, K. (2006) · Nature Protocols · doi:10.1038/nprot.2006.27 · Cited by 771 · see citing works
McKinnon, M. C., Yucel, K., Nazarov, A., & MacQueen, G. M. (2009) · Journal of Psychiatry and Neuroscience · doi:10.1139/jpn.0905 · Cited by 742 · see citing works
Gender differences in depression
Angst, J., Gamma, A., Gastpar, M., L�pine, J.-P., Mendlewicz, J., & Tylee, A. (2002) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-002-0381-6 · Cited by 629 · see citing works
Prenatal Poly(I:C) Exposure and Other Developmental Immune Activation Models in Rodent Systems
Meyer, U. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.07.011 · Cited by 626 · see citing works
Epigenetics: The link between nature and nurture
Tammen, S. A., Friso, S., & Choi, S. (2012) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2012.07.018 · Cited by 498 · see citing works
Gender differences in depression: Findings from the STAR*D study
Marcus, S. M., Young, E. A., Kerber, K. B., Kornstein, S., Farabaugh, A. H., Mitchell, J., Wisniewski, S. R., Balasubramani, G. K., Trivedi, M. H., & Rush, A. J. (2005) · Journal of Affective Disorders · doi:10.1016/j.jad.2004.09.008 · Cited by 456 · see citing works
Stuck in a rut: rethinking depression and its treatment
Holtzheimer, P. E., & Mayberg, H. S. (2010) · Trends in Neurosciences · doi:10.1016/j.tins.2010.10.004 · Cited by 431 · see citing works
Physical and Functional HAT/HDAC Interplay Regulates Protein Acetylation Balance
Peserico, A., & Simone, C. (2010) · BioMed Research International · doi:10.1155/2011/371832 · Cited by 362 · see citing works
BEBBINGTON, P. E., DUNN, G., JENKINS, R., LEWIS, G., BRUGHA, T., FARRELL, M., & MELTZER, H. (1998) · Psychological Medicine · doi:10.1017/s0033291797006077 · Cited by 330 · see citing works
Prenatal stress: Role in psychotic and depressive diseases
Markham, J. A., & Koenig, J. I. (2010) · Psychopharmacology · doi:10.1007/s00213-010-2035-0 · Cited by 274 · see citing works
Gene-Environment Interactions and Epigenetic Basis of Human Diseases
Liu, L., Li, Y., & Tollefsbol, T. O. (2008) · Current Issues in Molecular Biology · doi:10.21775/cimb.010.025 · Cited by 273 · see citing works
Silverstein, B. (1999) · American Journal of Psychiatry · doi:10.1176/ajp.156.3.480 · Cited by 268 · see citing works
Defeat stress in rodents: from behavior to molecules
Hammels, C., Pishva, E., De Vry, J., van den Hove, D. L. A., Prickaerts, J., van Winkel, R., Selten, J.-P., Lesch, K.-P., Daskalakis, N. P., Steinbusch, H. W. M., et al. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.10.006 · Cited by 230 · see citing works
Reisinger, S. N., Khan, D., Kong, E., Berger, A., Pollak, A. J., & Pollak, D. D. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.01.001 · Cited by 219 · see citing works
Self-citationBebbington, P., Dunn, G., Jenkins, R., Lewis, G., Brugha, T. S., Farrell, M., & Meltzer, H. (2003) · International Review of Psychiatry · doi:10.1080/0954026021000045976 · Cited by 216 · see citing works
High-Dimensional Mapping of the Hippocampus in Depression
Posener, J. A., Wang, L., Price, J. L., Gado, M. H., Province, M. A., Miller, M. I., Babb, C. M., & Csernansky, J. G. (2002) · American Journal of Psychiatry · doi:10.1176/appi.ajp.160.1.83 · Cited by 200 · see citing works
Serotonin transporter gene hypomethylation predicts impaired antidepressant treatment response
Domschke, K., Tidow, N., Schwarte, K., Deckert, J., Lesch, K., Arolt, V., Zwanzger, P., & Baune, B. T. (2014) · The International Journal of Neuropsychopharmacology · doi:10.1017/s146114571400039x · Cited by 179 · see citing works
Monje, F. J., Cabatic, M., Divisch, I., Kim, E.-J., Herkner, K. R., Binder, B. R., & Pollak, D. D. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.1537-11.2011 · Cited by 178 · see citing works
Self-citationHippocampal-dependent antidepressant-like activity of histone deacetylase inhibition
Covington, H. E., Vialou, V. F., LaPlant, Q., Ohnishi, Y. N., & Nestler, E. J. (2011) · Neuroscience Letters · doi:10.1016/j.neulet.2011.02.022 · Cited by 178 · see citing works
Haase, J. K., & Brown, E. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.10.002 · Cited by 173 · see citing works
Epigenetic signaling in psychiatric disorders: stress and depression
Bagot, R. C., Labonté, B., Peña, C. J., & Nestler, E. J. (2014) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2014.16.3/rbagot · Cited by 171 · see citing works
Schroeder, F. A., Lewis, M. C., Fass, D. M., Wagner, F. F., Zhang, Y.-L., Hennig, K. M., Gale, J., Zhao, W.-N., Reis, S., Barker, D. D., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0071323 · Cited by 146 · see citing works
Alonso, S. J., Castellano, M. A., Afonso, D., & Rodrı́guez, M. (1991) · Physiology & Behavior · doi:10.1016/0031-9384(91)90232-d · Cited by 133 · see citing works
Gender Differences in the Symptoms of Major Depressive Disorder
Romans, S. E., Tyas, J., Cohen, M. M., & Silverstone, T. (2007) · The Journal of Nervous and Mental Disease · doi:10.1097/nmd.0b013e3181594cb7 · Cited by 122 · see citing works
Long-term effects of maternal immune activation on depression-like behavior in the mouse
Khan, D., Fernando, P. M., Cicvaric, A., Berger, A., Pollak, A. J., Monje, F. J., & Pollak, D. D. (2014) · Translational Psychiatry · doi:10.1038/tp.2013.132 · Cited by 118 · see citing works
Self-citationPrenatal maternal immune activation causes epigenetic differences in adolescent mouse brain
Basil, P., Li, Q., Dempster, E. L., Mill, J., Sham, P.-C., Wong, C. C. Y., & McAlonan, G. M. (2014) · Translational Psychiatry · doi:10.1038/tp.2014.80 · Cited by 116 · see citing works
Connor, C., Dincer, A., Straubhaar, J., Galler, J. R., Houston, I. B., & Akbarian, S. (2012) · Schizophrenia Research · doi:10.1016/j.schres.2012.06.037 · Cited by 100 · see citing works
Epigenetic changes at gene promoters in response to immune activation in utero
Tang, B., Jia, H., Kast, R. J., & Thomas, E. A. (2013) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2013.01.086 · Cited by 91 · see citing works
Are there any gender differences in frequency of self-reported somatic symptoms of depression?
Wenzel, A. E., Steer, R. A., & Beck, A. T. (2005) · Journal of Affective Disorders · doi:10.1016/j.jad.2005.06.009 · Cited by 90 · see citing works
Beyond dsRNA: Toll-like receptor 3 signalling in RNA-induced immune responses
Tatematsu, M., Seya, T., & Matsumoto, M. (2014) · Biochemical Journal · doi:10.1042/bj20131492 · Cited by 75 · see citing works
Schmauss, C. (2015) · Scientific Reports · doi:10.1038/srep08171 · Cited by 70 · see citing works
A review of the adverse effects and safety of noradrenergic antidepressants
Whiskey, E., & Taylor, D. (2013) · Journal of Psychopharmacology · doi:10.1177/0269881113492027 · Cited by 64 · see citing works
Savalli, G., Diao, W., Berger, S., Ronovsky, M., Partonen, T., & Pollak, D. D. (2015) · Amino Acids · doi:10.1007/s00726-015-1968-3 · Cited by 45 · see citing works
Self-citationCircadian abnormalities in a mouse model of high trait anxiety and depression
Griesauer, I., Diao, W., Ronovsky, M., Elbau, I., Sartori, S. B., Singewald, N., & Pollak, D. D. (2014) · Annals of Medicine · doi:10.3109/07853890.2013.866440 · Cited by 40 · see citing works
Self-citationGómez, M. L., Martı́nez-Mota, L., Estrada-Camarena, E. M., & Fernández‐Guasti, A. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.12.035 · Cited by 37 · see citing works
Nucleosome signalling; An evolving concept
Turner, B. M. (2014) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2014.01.001 · Cited by 33 · see citing works
Simard, M., Côté, M., Provost, P. R., & Tremblay, Y. (2010) · Reproductive Biology and Endocrinology · doi:10.1186/1477-7827-8-134 · Cited by 16 · see citing works
Hau, J., & Jensen, H.-J. S. (1987) · Laboratory Animals · doi:10.1258/002367787781363372 · Cited by 14 · see citing works
Cellular plasticity and resilience and the pathophysiology of severe mood disorders
Charney, D. S., DeJesus, G., & Manji, H. K. (2004) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2004.6.2/dcharney · Cited by 12 · see citing works
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Neuroinflammation as a risk factor for attention deficit hyperactivity disorder
Dunn, G. A., Nigg, J. T., & Sullivan, E. L. (2019) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2019.05.005 · Cited by 299 · see citing works
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Hanswijk, S. I., Spoelder, M., Shan, L., Verheij, M. M. M., Muilwijk, O. G., Li, W., Liu, C., Kolk, S. M., & Homberg, J. R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165850 · Cited by 86 · see citing works
- Authors
- Reisinger, S. N., Kong, E., Khan, D., Schulz, S., Ronovsky, M., Berger, S., Horvath, O., Cabatic, M., Berger, A., & Pollak, D. D.
- Affiliations
- Medical University of Vienna (AT)
- Corresponding author
- Pollak, Daniela D.
- Venue
- Neurobiology of Stress
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 4
- Pages
- 34-43
- ISSN
- 2352-2895 (ISSN-L)
- PMC
- PMC5146201
- OpenAlex
- W2283818958
- Cited by
- 62
- References
- 52
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 4 · 2023: 5 · 2022: 8 · 2021: 7 · 2020: 7 · 2019: 8 · 2018: 10 · 2017: 1 · 2016: 2
- FWCI
- 4.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neurobiology of Stress (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Austrian Science Fund (FWF) (F3516-B20, P 27520)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- maternal immune activation, major depressive disorder, serotonin transporter, hippocampus, histone acetylation, HDAC1, early life stress, anhedonia, depression-like behavior, epigenetic regulation, antidepressant targets, poly(I:C)
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