Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in the MAM model for schizophrenia
Open accessAbstract
Schizophrenia (SCZ) is characterized not only by psychosis, but also by working memory and executive functioning deficiencies, processes that rely on the prefrontal cortex (PFC). Because these cognitive impairments emerge prior to psychosis onset, we investigated synaptic function during development in the neurodevelopmental methylazoxymethanol (MAM) model for SCZ. Specifically, we hypothesize that N‐methyl‐D‐aspartate receptor (NMDAR) hypofunction is attributable to reductions in the NR 2B subunit through aberrant epigenetic regulation of gene expression, resulting in deficient synaptic physiology and PFC‐dependent cognitive dysfunction, a hallmark of SCZ. Using western blot and whole‐cell patch‐clamp electrophysiology, we found that the levels of synaptic NR 2B protein are significantly decreased in juvenile MAM animals, and the function of NMDAR s is substantially compromised. Both NMDA‐mEPSC s and synaptic NMDA‐eEPSC s are significantly reduced in prelimbic PFC (pl PFC). This protein loss during the juvenile period is correlated with an aberrant increase in enrichment of the epigenetic transcriptional repressor RE1‐silencing transcription factor (REST) and the repressive histone marker H3K27me3 at the Grin2b promoter, as assayed by Ch IP‐quantitative polymerase chain reaction. Glutamate hypofunction has been a prominent hypothesis in the understanding of SCZ pathology; however, little attention has been given to the NMDAR system in the developing PFC in models for SCZ. Our work is the first to confirm that NMDAR hypofunction is a feature of early postnatal development, with epigenetic hyper‐repression of the Grin2b promoter being a contributing factor. The selective loss of NR 2B protein and subsequent synaptic dysfunction weakens pl PFC function during development and may underlie early cognitive impairments in SCZ models and patients. image Read the Editorial Highlight for this article on page 264.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
In a rat model of SZ, abnormal epigenetic repression of NMDAR subunit Grin2b in PFC drives glutamatergic synaptic deficits.
“In a rat model of SZ, abnormal epigenetic repression of the NMDAR subunit Grin2b in PFC drives glutamatergic synaptic deficits 201.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [201]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The adolescent brain and age-related behavioral manifestations
Spear, L. P. (2000) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(00)00014-2 · Cited by 5,433 · 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
Cellular basis of working memory
Goldman-Rakic, P. S. (1995) · Neuron · doi:10.1016/0896-6273(95)90304-6 · Cited by 2,663 · see citing works
NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease
Paoletti, P., Bellone, C., & Zhou, Q. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3504 · Cited by 2,523 · see citing works
Genetic enhancement of learning and memory in mice
Tang, Y., Shimizu, E., Dubé, G., Rampon, C., Kerchner, G. A., Zhuo, M., Liu, G., & Tsien, J. Z. (1999) · Nature · doi:10.1038/43432 · Cited by 1,867 · see citing works
De novo mutations in schizophrenia implicate synaptic networks
Fromer, M., Pocklington, A. J., Kavanagh, D. H., Williams, H. J., Dwyer, S., Gormley, P., Georgieva, L., Rees, E., Palta, P., Ruderfer, D. M., et al. (2014) · Nature · doi:10.1038/nature12929 · Cited by 1,617 · see citing works
Geyer, M. A., Krebs-Thomson, K., Braff, D. L., & Swerdlow, N. R. (2001) · Psychopharmacology · doi:10.1007/s002130100811 · Cited by 1,484 · see citing works
Child developmental risk factors for adult schizophrenia in the British 1946 birth cohort
JONES, P. (1994) · The Lancet · doi:10.1016/s0140-6736(94)90569-x · Cited by 1,353 · see citing works
NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders
Lau, C. G., & Zukin, R. S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2153 · Cited by 1,159 · see citing works
To Model a Psychiatric Disorder in Animals Schizophrenia As a Reality Test
Lipska, B. K. (2000) · Neuropsychopharmacology · doi:10.1016/s0893-133x(00)00137-8 · Cited by 650 · see citing works
Cognitive deficits and functional outcome in schizophrenia
Bowie, C. R., & Harvey, P. D. (2006) · Neuropsychiatric Disease and Treatment · doi:10.2147/nedt.2006.2.4.531 · Cited by 647 · see citing works
Endele, S., Rosenberger, G., Geider, K., Popp, B., Tamer, C., Stefanova, I., Milh, M., Kortüm, F., Fritsch, A., Pientka, F. K., et al. (2010) · Nature Genetics · doi:10.1038/ng.677 · Cited by 499 · see citing works
Wang, M., Yang, Y., Wang, C.-J., Gamo, N. J., Jin, L. E., Mazer, J. A., Morrison, J. H., Wang, X.-J., & Arnsten, A. F. T. (2013) · Neuron · doi:10.1016/j.neuron.2012.12.032 · Cited by 489 · see citing works
Glutamate receptor expression in schizophrenic brain
Meador‐Woodruff, J. H. (2000) · Brain Research Reviews · doi:10.1016/s0165-0173(99)00044-2 · Cited by 412 · see citing works
Kantrowitz, J. T., & Javitt, D. C. (2010) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2010.04.006 · Cited by 397 · see citing works
Moore, H. M., Jentsch, J. D., Ghajarnia, M., Geyer, M. A., & Grace, A. A. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.01.003 · Cited by 359 · see citing works
Laruelle, M. (2000) · Brain research. Brain research reviews · doi:10.1016/s0165-0173(99)00054-5 · Cited by 347 · see citing works
Epigenetic basis of mental illness
Nestler, E. J., Peña, C. J., Kundakovic, M., Mitchell, A., & Akbarian, S. (2016) · The Neuroscientist · doi:10.1177/1073858415608147 · Cited by 342 · see citing works
Regulation of gene transcription by Polycomb proteins
Aranda, S., Martín, G. M., & Croce, L. D. (2015) · Science Advances · doi:10.1126/sciadv.1500737 · Cited by 332 · see citing works
The assessment of neuropsychological functioning in schizophrenia
Reichenberg, A. (2010) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2010.12.3/areichenberg · Cited by 270 · see citing works
Neuropsychological evidence for frontostriatal dysfunction in schizophrenia
Elliott, R., McKenna, P. J., Robbins, T. W., & Sahakian, B. J. (1995) · Psychological Medicine · doi:10.1017/s0033291700033523 · Cited by 267 · see citing works
Treating Working Memory Deficits in Schizophrenia: A Review of the Neurobiology
Lett, T. A., Voineskos, A. N., Kennedy, J. L., Levine, B., & Daskalakis, Z. J. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.07.026 · Cited by 257 · see citing works
Beneyto, M., & Meador‐Woodruff, J. H. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301604 · Cited by 255 · see citing works
Cannon, T. D., Bearden, C. E., Hollister, J. M., Rosso, I. M., Sanchez, L. E., & Hadley, T. R. (2000) · Schizophrenia Bulletin · doi:10.1093/oxfordjournals.schbul.a033460 · Cited by 250 · see citing works
NMDA hypofunction as a convergence point for progression and symptoms of schizophrenia
Snyder, M. A., & Gao, W. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00031 · Cited by 237 · see citing works
Self-citationMolecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia
Weickert, C. S., Fung, S. J., Catts, V. S., Schofield, P. R., Allen, K. M., Moore, L., Newell, K. A., Pellen, D., Huang, X.-F., Catts, S. V., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2012.137 · Cited by 234 · see citing works
Lodge, D. J., & Grace, A. A. (2009) · Behavioural Brain Research · doi:10.1016/j.bbr.2009.01.031 · Cited by 215 · see citing works
Flagstad, P., Mørk, A., Glenthøj, B., van Beek, J., Michael-Titus, A., & Didriksen, M. (2004) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300516 · Cited by 210 · see citing works
Genetic animal models: focus on schizophrenia
Gainetdinov, R. R., Mohn, A. R., & Caron, M. G. (2001) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01886-5 · Cited by 201 · see citing works
Wang, H., Stradtman, G. G., Wang, X.-J., & Gao, W.-J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0804318105 · Cited by 199 · see citing works
REST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors
Rodenas-Ruano, A., Chávez, A. E., Cossio, M. J., Castillo, P. E., & Zukin, R. S. (2012) · Nature Neuroscience · doi:10.1038/nn.3214 · Cited by 198 · see citing works
Cell Type-Specific Development of NMDA Receptors in the Interneurons of Rat Prefrontal Cortex
Wang, H.-X., & Gao, W. (2009) · Neuropsychopharmacology · doi:10.1038/npp.2009.20 · Cited by 198 · see citing works
Self-citationGilmour, G., Dix, S. L., Fellini, L., Gastambide, F., Plath, N., Steckler, T., Talpos, J. C., & Tricklebank, M. D. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.03.015 · Cited by 183 · see citing works
Dumas, T. C. (2005) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2005.08.002 · Cited by 169 · see citing works
Rosso, I. M., Bearden, C. E., Hollister, J. M., Gasperoni, T. L., Sanchez, L. E., Hadley, T. R., & Cannon, T. D. (2000) · Schizophrenia Bulletin · doi:10.1093/oxfordjournals.schbul.a033459 · Cited by 155 · see citing works
Glutamatergic transmission in schizophrenia
Kantrowitz, J. T., & Javitt, D. C. (2012) · Current Opinion in Psychiatry · doi:10.1097/yco.0b013e32835035b2 · Cited by 155 · see citing works
Martucci, L., Wong, A. H. C., Luca, V. D., Likhodi, O., Wong, G. W. H., King, N. A., & Kennedy, J. L. (2006) · Schizophrenia Research · doi:10.1016/j.schres.2006.02.001 · Cited by 137 · see citing works
Cui, Y., Jin, J., Zhang, X., Xu, H., Yang, L., Du, D., Zeng, Q., Tsien, J. Z., Yu, H., & Cao, X. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020312 · Cited by 132 · see citing works
Working memory deficits in adult rats after prenatal disruption of neurogenesis
Gourévitch, R., Rocher, C., Pen, G. L., Krebs, M., & Jay, T. M. (2004) · Behavioural Pharmacology · doi:10.1097/01.fbp.0000135703.48799.71 · Cited by 126 · see citing works
Ionotropic Glutamate Receptors as Therapeutic Targets in Schizophrenia
Coyle, J. T., Tsai, G. E., & GOFF, D. C. (2002) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1568007024606212 · Cited by 126 · see citing works
Jiang, Y., Jakovcevski, M., Bharadwaj, R., Connor, C., Schroeder, F. A., Lin, C. L., Straubhaar, J., Martin, G., & Akbarian, S. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.1314-10.2010 · Cited by 118 · see citing works
Jia, P., Wang, L., Fanous, A. H., Pato, C. N., Edwards, T. L., & Zhao, Z. (2012) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002587 · Cited by 110 · see citing works
Wang, H. X., & Gao, W. (2010) · The Journal of Physiology · doi:10.1113/jphysiol.2010.187591 · Cited by 109 · see citing works
Self-citationFlagstad, P., Glenthoj, B. Y., & Didriksen, M. (2004) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300625 · Cited by 107 · see citing works
Qin, S., Zhao, X., Pan, Y., Liu, J., Feng, G., Fu, J., Bao, J., Zhang, Z., & He, L. (2005) · European Journal of Human Genetics · doi:10.1038/sj.ejhg.5201418 · Cited by 105 · see citing works
Stadler, F. J., Kolb, G., Rubusch, L., Baker, S. P., Jones, E. G., & Akbarian, S. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03190.x · Cited by 98 · see citing works
Monaco, S. A., Gulchina, Y., & Gao, W. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.06.022 · Cited by 92 · see citing works
Self-citationEpigenetic mechanisms in schizophrenia
Akbarian, S. (2014) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2014.16.3/sakbarian · Cited by 89 · see citing works
Kano, S., Colantuoni, C., Han, F., Zhou, Z., Yuan, Q., Wilson, A., Takayanagi, Y., Lee, Y., Rapoport, J. L., Eaton, W. W., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2012.120 · Cited by 88 · see citing works
Recruitment and Biological Consequences of Histone Modification of H3K27me3 and H3K9me3
Kim, J. H., & Kim, H. (2012) · ILAR Journal · doi:10.1093/ilar.53.3-4.232 · Cited by 86 · see citing works
Jeevakumar, V., Driskill, C., Paine, A., Sobhanian, M., Vakil, H., Morris, B., Ramos, J., & Kroener, S. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2015.01.010 · Cited by 84 · see citing works
Conserved Higher-Order Chromatin Regulates NMDA Receptor Gene Expression and Cognition
Bharadwaj, R., Peter, C. J., Jiang, Y., Roussos, P., Vogel-Ciernia, A., Shen, E. Y., Mitchell, A. C., Mao, W., Whittle, C., Dincer, A., et al. (2014) · Neuron · doi:10.1016/j.neuron.2014.10.032 · Cited by 84 · see citing works
Numata, S., Ye, T., Herman, M., & Lipska, B. K. (2014) · Frontiers in Genetics · doi:10.3389/fgene.2014.00280 · Cited by 70 · see citing works
Lavı́n, A., Moore, H. M., & Grace, A. A. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300696 · Cited by 62 · see citing works
Hradetzky, E., Sanderson, T. M., Tsang, T. M., Sherwood, J. L., Fitzjohn, S. M., Lakics, V., Malik, N. K., Schoeffmann, S., O’Neill, M. J., Cheng, T. M., et al. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2011.219 · Cited by 61 · see citing works
Akbarian, S. (2010) · Current topics in behavioral neurosciences · doi:10.1007/7854_2010_38 · Cited by 57 · see citing works
Marquis, J., Goulet, S., & Doré, F. Y. (2008) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2008.04.005 · Cited by 57 · see citing works
Kristiansen, L. V., Bakir, B., Haroutunian, V. H., & Meador‐Woodruff, J. H. (2010) · Schizophrenia Research · doi:10.1016/j.schres.2010.02.1069 · Cited by 54 · see citing works
Maćkowiak, M., Bator, E., Latusz, J., Mordalska, P., & Wędzony, K. (2013) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2013.05.013 · Cited by 51 · see citing works
The molecular pathology of schizophrenia—Focus on histone and DNA modifications
Akbarian, S. (2009) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2009.08.018 · Cited by 43 · see citing works
Snyder, M. A., Adelman, A. E., & Gao, W. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.180 · Cited by 37 · see citing works
Self-citationTamminga, C. A., & Zukin, R. S. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.07.038 · Cited by 33 · see citing works
Xing, B., Li, Y., & Gao, W. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2016.110 · Cited by 32 · see citing works
Self-citationMarquis, J., Goulet, S.-M., & Doré, F. Y. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.02.048 · Cited by 25 · see citing works
Li, M. S., Gulchina, Y., Monaco, S. A., Xing, B., Ferguson, B. R., Li, Y., Li, F., Hu, X., & Gao, W. (2017) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2017.02.004 · Cited by 19 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Yan, Z., & Rein, B. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01092-3 · Cited by 300 · see citing works
- Authors
- Gulchina, Y., Xu, S., Snyder, M. A., Elefant, F., & Gao, W.
- Affiliations
- Drexel University (US)
- Corresponding author
- Gao, Wen‐Jun
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2017-09-05
- Volume
- 143
- Issue
- 3
- Pages
- 320-333
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- PMC
- PMC5653427
- OpenAlex
- W2698520775
- Cited by
- 56
- References
- 65
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 2 · 2023: 5 · 2022: 13 · 2021: 7 · 2020: 8 · 2019: 5 · 2018: 7 · 2017: 1
- FWCI
- 4.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01MH085666)
- National Alliance for Research on Schizophrenia and Depression
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- schizophrenia, NMDA receptor hypofunction, NR2B subunit, prefrontal cortex, epigenetic regulation, rest, H3K27me3, synaptic transmission, cognitive impairment, brain development, prelimbic cortex, juvenile development
- MeSH terms
- Animals, Animals, Newborn, Cognition Disorders, Disease Models, Animal, Female, Male, Methylazoxymethanol Acetate, Neurons, Pregnancy, Schizophrenia, Receptors, N-Methyl-D-Aspartate, N-Methylaspartate, Prefrontal Cortex, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, Patch-Clamp Techniques, Gene Expression Regulation, Developmental, Excitatory Amino Acid Agonists, Excitatory Postsynaptic Potentials, Epigenesis, Genetic, Rats, In Vitro Techniques
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
