Phosphorylation of MeCP2 at Ser421 Contributes to Chronic Antidepressant Action
Open accessAbstract
Although tricyclic antidepressants rapidly activate monoaminergic neurotransmission, these drugs must be administered chronically to alleviate symptoms of depression. This observation suggests that molecular mechanisms downstream of monoamine receptor activation, which include the induction of gene transcription, underlie chronic antidepressant-induced changes in behavior. Here we show that methyl-CpG-binding protein 2 (MeCP2) regulates behavioral responses to chronic antidepressant treatment. Imipramine administration induces phosphorylation of MeCP2 at Ser421 (pMeCP2) selectively in the nucleus accumbens and the lateral habenula, two brain regions important for depressive-like behaviors. To test the role of pMeCP2 in depressive-like behaviors, we used male mice that bear a germ-line mutation knocked into the X-linked Mecp2 locus that changes Ser421 to a nonphosphorylatable Ala residue (S421A). MeCP2 S421A knock-in (KI) mice showed increased immobility in forced-swim and tail-suspension tests compared with their wild-type (WT) littermates. However, immobility of both MeCP2 WT and KI mice in forced swim was reduced by acute administration of imipramine, demonstrating that loss of pMeCP2 does not impair acute pharmacological sensitivity to this drug. After chronic social defeat stress, chronic administration of imipramine significantly improved social interaction in the MeCP2 WT mice. In contrast, the MeCP2 KI mice did not respond to chronic imipramine administration. These data suggest novel roles for pMeCP2 in the sensitivity to stressful stimuli and demonstrate that pMeCP2 is required for the effects of chronic imipramine on depressive-like behaviors induced by chronic social defeat stress.
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MeCP2 Ser421 phosphorylation is required for the long-lasting antidepressant effects of ketamine but not for the initial rapid antidepressant response.
“While MeCP2 Ser421 phosphorylation is required for these long-lasting effects, it is not required for the initial rapid antidepressant response [78,80].”
From Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review (2024) · cites this paper as [80]
The Discussion reports that MeCP2 Ser421 phosphorylation is required for the response to chronic imipramine, while mice lacking it still respond to acute imipramine. That supports an acute-versus-chronic distinction for imipramine, not ketamine. The Discussion explicitly says whether ketamine requires this phosphorylation for its behavioral effects remains to be determined; no page number is available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSome results are derived from secondary analyses of previously conducted studies, so the setting may not be optimal for examining BDNF variations in patients treated with ketamine.
“some of the results presented are derived from secondary analyses of previously conducted studies [80,83]; therefore, the setting may not be optimal for the objective considered (examining BDNF variations in patients treated with ketamine).”
From Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review (2024) · cites this paper as [80]
The Discussion mentions ketamine only as a rapid-acting antidepressant and says its dependence on MeCP2 phosphorylation remains undetermined. The Results describe experiments in mice treated with imipramine, not secondary analyses of BDNF variation in patients treated with ketamine. I searched for secondary analyses, BDNF, and ketamine-treated patients; our copy does not address the attributed point. (LLM, conf=0.76)
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Cites
Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2
Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., & Zoghbi, H. Y. (1999) · Nature Genetics · doi:10.1038/13810 · Cited by 4,990 · see citing works
Depression: a new animal model sensitive to antidepressant treatments
PORSOLT, R. D., LE PICHON, M., & JALFRE, M. (1977) · Nature · doi:10.1038/266730a0 · Cited by 4,451 · see citing works
Antidepressant effects of ketamine in depressed patients
Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00230-9 · Cited by 3,856 · see citing works
A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
Zarate, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., Charney, D. S., & Manji, H. K. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.8.856 · Cited by 3,766 · see citing works
The tail suspension test: A new method for screening antidepressants in mice
Steru, L., Chermat, R., Thierry, B., & Simon, P. (1985) · Psychopharmacology · doi:10.1007/bf00428203 · Cited by 3,534 · 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
Krishnan, V., Han, M.-H., Graham, D. L., Berton, O., Renthal, W., Russo, S. J., LaPlant, Q., Graham, A., Lutter, M., Lagace, D. C., et al. (2007) · Cell · doi:10.1016/j.cell.2007.09.018 · Cited by 2,307 · see citing works
Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress
Berton, O., McClung, C. A., DiLeone, R. J., Krishnan, V., Renthal, W., Russo, S. J., Graham, D., Tsankova, N. M., Bolanos, C. A., Rios, M., et al. (2006) · Science · doi:10.1126/science.1120972 · Cited by 2,129 · see citing works
The mesolimbic dopamine reward circuit in depression
Nestler, E. J., & Carlezon, W. A. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.09.018 · Cited by 2,059 · see citing works
NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses
Autry, A. E., Adachi, M., Nosyreva, E., Na, E. S., Los, M. F., Cheng, P.-F., Kavalali, E. T., & Monteggia, L. M. (2011) · Nature · doi:10.1038/nature10130 · Cited by 1,926 · see citing works
MeCP2, a Key Contributor to Neurological Disease, Activates and Represses Transcription
Chahrour, M., Jung, S. Y., Shaw, C., Zhou, X., Wong, S. T. C., Qin, J., & Zoghbi, H. Y. (2008) · Science · doi:10.1126/science.1153252 · Cited by 1,823 · see citing works
Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action
Tsankova, N. M., Berton, O., Renthal, W., Kumar, A., Neve, R. L., & Nestler, E. J. (2006) · Nature Neuroscience · doi:10.1038/nn1659 · Cited by 1,780 · see citing works
A standardized protocol for repeated social defeat stress in mice
Golden, S. A., Covington, H. E., Berton, O., & Russo, S. J. (2011) · Nature Protocols · doi:10.1038/nprot.2011.361 · Cited by 1,581 · 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
The cellular neurobiology of depression
Manji, H. K., Drevets, W. C., & Charney, D. S. (2001) · Nature Medicine · doi:10.1038/87865 · Cited by 1,182 · see citing works
Li, N., Liu, R.-J., Dwyer, J. M., Banasr, M., Lee, B., Son, H., Li, X.-Y., Aghajanian, G., & Duman, R. S. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.12.015 · Cited by 1,082 · see citing works
The habenula: from stress evasion to value-based decision-making
Hikosaka, O. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2866 · Cited by 955 · see citing works
Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders
Sanacora, G., Zarate, C. A., Krystal, J. H., & Manji, H. K. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2462 · Cited by 894 · see citing works
Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward
Lobo, M. K., Covington, H. E., Chaudhury, D., Friedman, A. K., Sun, H., Damez-Werno, D., Dietz, D. M., Zaman, S., Koo, J. W., Kennedy, P. J., et al. (2010) · Science · doi:10.1126/science.1188472 · Cited by 880 · see citing works
Zhou, Z., Hong, E. J., Cohen, S., Zhao, W.-N., Ho, H.-Y. H., Schmidt, L., Chen, W. G., Lin, Y., Savner, E., Griffith, E. C., et al. (2006) · Neuron · doi:10.1016/j.neuron.2006.09.037 · Cited by 877 · see citing works
Self-citationInhibitory control of neostriatal projection neurons by GABAergic interneurons
Koós, T. Z., & Tepper, J. M. (1999) · Nature Neuroscience · doi:10.1038/8138 · Cited by 851 · see citing works
Neuronal MeCP2 Is Expressed at Near Histone-Octamer Levels and Globally Alters the Chromatin State
Skene, P. J., Illingworth, R. S., Webb, S., Kerr, A. R. W., James, K. D., Turner, D. J., Andrews, R., & Bird, A. P. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.01.030 · Cited by 688 · see citing works
Synaptic potentiation onto habenula neurons in the learned helplessness model of depression
Li, B., Piriz, J., Mirrione, M., Chung, C., Proulx, C. D., Schulz, D., Henn, F., & Malinow, R. (2011) · Nature · doi:10.1038/nature09742 · Cited by 634 · see citing works
Antidepressant Actions of Histone Deacetylase Inhibitors
Covington, H. E., Maze, I., LaPlant, Q. C., Vialou, V. F., Ohnishi, Y. N., Berton, O., Fass, D. M., Renthal, W., Rush, A. J., Wu, E. Y., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.1758-09.2009 · Cited by 624 · see citing works
THE TREATMENT OF DEPRESSIVE STATES WITH G 22355 (IMIPRAMINE HYDROCHLORIDE)
Kuhn, R. (1958) · American Journal of Psychiatry · doi:10.1176/ajp.115.5.459 · Cited by 615 · see citing works
Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens
LaPlant, Q., Vialou, V., Covington, H. E., Dumitriu, D., Feng, J., Warren, B. L., Maze, I., Dietz, D. M., Watts, E. L., Iñiguez, S. D., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2619 · Cited by 612 · see citing works
Histone Deacetylase 5 Epigenetically Controls Behavioral Adaptations to Chronic Emotional Stimuli
Renthal, W., Maze, I., Krishnan, V., Covington, H. E., Xiao, G., Kumar, A., Russo, S. J., Graham, A., Tsankova, N., Kippin, T. E., et al. (2007) · Neuron · doi:10.1016/j.neuron.2007.09.032 · Cited by 599 · see citing works
Representation of negative motivational value in the primate lateral habenula
Matsumoto, M., & Hikosaka, O. (2009) · Nature Neuroscience · doi:10.1038/nn.2233 · Cited by 547 · see citing works
Barrot, M., Olivier, J. D. A., Perrotti, L. I., DiLeone, R. J., Berton, O., Eisch, A. J., Impey, S., Storm, D. R., Neve, R. L., Yin, J. C., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.172091899 · Cited by 508 · see citing works
cAMP Response Element-Mediated Gene Transcription Is Upregulated by Chronic Antidepressant Treatment
Thome, J., Sakai, N., Shin, K.-H., Steffen, C., Zhang, Y.-J., Impey, S., Storm, D. R., & Duman, R. S. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-11-04030.2000 · Cited by 507 · see citing works
Ullsperger, M., & von Cramon, D. Y. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-10-04308.2003 · Cited by 484 · see citing works
Dulawa, S. C., & Hen, R. (2005) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2005.03.017 · Cited by 431 · see citing works
Furey, M. L., & Drevets, W. C. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.10.1121 · Cited by 417 · see citing works
The Role of MeCP2 in the Brain
Guy, J., Cheval, H., Selfridge, J., & Bird, A. P. (2011) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-092910-154121 · Cited by 414 · see citing works
Social model of depression in mice of C57BL/6J strain
Kudryavtseva, N. N., Bakshtanovskaya, I. V., & Koryakina, L. A. (1991) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(91)90284-9 · Cited by 404 · see citing works
Hong, S., Jhou, T. C., Smith, M., Saleem, K. S., & Hikosaka, O. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.1384-11.2011 · Cited by 390 · see citing works
Ji, H., & Shepard, P. D. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.0958-07.2007 · Cited by 388 · see citing works
Distinct Roles of GABAergic Interneurons in the Regulation of Striatal Output Pathways
Gittis, A. H., Nelson, A., Thwin, M. T., Palop, J. J., & Kreitzer, A. C. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.4870-09.2010 · Cited by 364 · see citing works
Induction of ΔFosB in Reward-Related Brain Structures after Chronic Stress
Perrotti, L. I., Hadeishi, Y., Ulery, P. G., Barrot, M., Monteggia, L. M., Duman, R. S., & Nestler, E. J. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.2542-04.2004 · Cited by 330 · see citing works
Cohen, S., Gabel, H. W., Hemberg, M., Hutchinson, A. N., Sadacca, L. A., Ebert, D. H., Harmin, D. A., Greenberg, R. S., Verdine, V. K., Zhou, Z., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.08.022 · Cited by 298 · see citing works
Self-citationCovariation of activity in habenula and dorsal raphe nuclei following tryptophan depletion
Morris, J. S., Smith, K. A., Cowen, P. J., Friston, K. J., & Dolan, R. J. (1999) · NeuroImage · doi:10.1006/nimg.1999.0455 · Cited by 288 · see citing works
Lecourtier, L., & Kelly, P. H. (2007) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2007.01.004 · Cited by 283 · see citing works
Lateral habenula neurons signal errors in the prediction of reward information
Bromberg-Martin, E. S., & Hikosaka, O. (2011) · Nature Neuroscience · doi:10.1038/nn.2902 · Cited by 275 · see citing works
Wilkinson, M. B., Xiao, G., Kumar, A., LaPlant, Q., Renthal, W., Sikder, D., Kodadek, T. J., & Nestler, E. J. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.0932-09.2009 · Cited by 262 · see citing works
Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses
Goffin, D., Allen, M., Zhang, L., Amorim, M., Wang, I.-T. J., Reyes, A.-R. S., Mercado-Berton, A., Ong, C., Cohen, S., Hu, L., et al. (2012) · Nature Neuroscience · doi:10.1038/nn.2997 · Cited by 226 · see citing works
Self-citationMeCP2 in the nucleus accumbens contributes to neural and behavioral responses to psychostimulants
Deng, J. V., Rodriguiz, R. M., Hutchinson, A. N., Kim, I.-H., Wetsel, W. C., & West, A. E. (2010) · Nature Neuroscience · doi:10.1038/nn.2614 · Cited by 206 · see citing works
Self-citationStahl, S. M. (2003) · PubMed · Cited by 180 · see citing works
Stahl, S. M. (2003) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v64n0301 · Cited by 154 · see citing works
Kalén, P., Karlson, M., & Wiklund, L. (1985) · Brain Research · doi:10.1016/0006-8993(85)91244-2 · Cited by 148 · see citing works
Vmat2 Heterozygous Mutant Mice Display a Depressive-Like Phenotype
Fukui, M., Rodriguiz, R. M., Zhou, J., Jiang, X. “., Phillips, L. E., Caron, M. G., & Wetsel, W. C. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.4388-06.2007 · Cited by 147 · 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
Richelson, E. (2003) · PubMed · Cited by 102 · see citing works
Nishikawa, T., & Scatton, B. (1985) · Brain Research · doi:10.1016/0006-8993(85)90717-6 · Cited by 102 · see citing works
Serum Response Factor Promotes Resilience to Chronic Social Stress through the Induction of ΔFosB
Vialou, V., Maze, I., Renthal, W., LaPlant, Q. C., Watts, E. L., Mouzon, E., Ghose, S., Tamminga, C. A., & Nestler, E. J. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.2496-10.2010 · Cited by 91 · see citing works
Differential Regulation of MeCP2 Phosphorylation in the CNS by Dopamine and Serotonin
Hutchinson, A. N., Deng, J. V., Aryal, D. K., Wetsel, W. C., & West, A. E. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2011.190 · Cited by 31 · see citing works
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Epigenetics and the regulation of stress vulnerability and resilience
Zannas, A. S., & West, A. E. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2013.12.003 · Cited by 211 · see citing works
Self-citationTadić, A., Müller-Engling, L., Schlicht, K. F., Kotsiari, A., Dreimüller, N., Kleimann, A., Bleich, S., Lieb, K., & Frieling, H. (2014) · Molecular Psychiatry · doi:10.1038/mp.2013.58 · Cited by 175 · see citing works
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Dionisie, V., Ciobanu, A. M., Toma, V. A., Manea, M. C., Baldea, I., Olteanu, D., Sevastre-Berghian, A., Clichici, S., Manea, M., Riga, S., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147483 · Cited by 78 · see citing works
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- Authors
- Hutchinson, A. N., Deng, J. V., Cohen, S., & West, A. E.
- Affiliations
- Duke Medical Center (US)
- Harvard University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-10-10
- Volume
- 32
- Issue
- 41
- Pages
- 14355-14363
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3480513
- OpenAlex
- W2066854681
- Cited by
- 53
- References
- 55
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 7 · 2021: 4 · 2020: 3 · 2019: 3 · 2018: 5 · 2017: 4 · 2016: 3 · 2015: 4 · 2014: 8 · 2013: 4 · 2012: 1
- FWCI
- 3.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (F31MH090754, R21MH096310)
- National Institute on Drug Abuse (R01DA022202)
- National Institute of General Medical Sciences (T32GM007753)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- MeCP2, chronic antidepressant treatment, imipramine, depression, social defeat stress, nucleus accumbens, lateral habenula, depression-like behavior, gene transcription
- MeSH terms
- Animals, Antidepressive Agents, Depression, Male, Mice, Inbred C57BL, Mice, Transgenic, Phosphorylation, Serine, Social Environment, Time Factors, Mice, Methyl-CpG-Binding Protein 2, Gene Knock-In Techniques
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