A TrkB Small Molecule Partial Agonist Rescues TrkB Phosphorylation Deficits and Improves Respiratory Function in a Mouse Model of Rett Syndrome
Open accessAbstract
Rett syndrome (RTT) results from loss-of-function mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2) and is characterized by abnormal motor, respiratory and autonomic control, cognitive impairment, autistic-like behaviors and increased risk of seizures. RTT patients and Mecp2 -null mice exhibit reduced expression of brain-derived neurotrophic factor (BDNF), which has been linked in mice to increased respiratory frequency, a hallmark of RTT. The present study was undertaken to test the hypotheses that BDNF deficits in Mecp2 mutants are associated with reduced activation of the BDNF receptor, TrkB, and that pharmacologic activation of TrkB would improve respiratory function. We characterized BDNF protein expression, TrkB activation and respiration in heterozygous female Mecp2 mutant mice (Het), a model that recapitulates the somatic mosaicism for mutant MECP2 found in typical RTT patients, and evaluated the ability of a small molecule TrkB agonist, LM22A-4, to ameliorate biochemical and functional abnormalities in these animals. We found that Het mice exhibit (1) reduced BDNF expression and TrkB activation in the medulla and pons and (2) breathing dysfunction, characterized by increased frequency due to periods of tachypnea, and increased apneas, as in RTT patients. Treatment of Het mice with LM22A-4 for 4 weeks rescued wild-type levels of TrkB phosphorylation in the medulla and pons and restored wild-type breathing frequency. These data provide new insight into the role of BDNF signaling deficits in the pathophysiology of RTT and highlight TrkB as a possible therapeutic target in this disease.
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LM22A-4 reverses respiratory abnormalities and improves functional recovery after stroke.
“It was first shown as an effective molecule to reverse respiratory abnormalities (Kron et al. 2014; Schmid et al. 2012) and to improve functional recovery after stroke (Han et al. 2012).”
From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as Schmid et al. 2012
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Cites
Bradford, M. M. (1976) · Analytical Biochemistry · doi:10.1016/0003-2697(76)90527-3 · Cited by 255,302 · see citing works
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
A Neurotrophic Model for Stress-Related Mood Disorders
Duman, R. S., & Monteggia, L. M. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.02.013 · Cited by 3,375 · see citing works
Trk Receptors: Roles in Neuronal Signal Transduction
Huang, E. J., & Reichardt, L. F. (2003) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.72.121801.161629 · Cited by 2,537 · 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
The Story of Rett Syndrome: From Clinic to Neurobiology
Chahrour, M., & Zoghbi, H. Y. (2007) · Neuron · doi:10.1016/j.neuron.2007.10.001 · Cited by 1,265 · see citing works
Derepression of BDNF Transcription Involves Calcium-Dependent Phosphorylation of MeCP2
Chen, W. G., Chang, Q., Lin, Y., Meissner, A., West, A. E., Griffith, E. C., Jaenisch, R., & Greenberg, M. E. (2003) · Science · doi:10.1126/science.1086446 · Cited by 1,232 · see citing works
p75 and Trk: A two-receptor system
Chao, M. V., & Hempstead, B. L. (1995) · Trends in Neurosciences · doi:10.1016/0166-2236(95)93922-k · Cited by 857 · see citing works
Shahbazian, M. D., Young, J. I., Yuva‐Paylor, L. A., Spencer, C. M., Antalffy, B. A., Noebels, J. L., Armstrong, D. L., Paylor, R. E., & Zoghbi, H. Y. (2002) · Neuron · doi:10.1016/s0896-6273(02)00768-7 · Cited by 760 · see citing works
A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone
Jang, S., Liu, X., Yepes, M., Shepherd, K. R., Miller, G. W., Liu, Y., Wilson, W. D., Xiao, G., Blanchi, B., Sun, Y. E., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0913572107 · Cited by 689 · see citing works
Neurotrophin signalling in health and disease
Chao, M. V., Rajagopal, R., & Lee, F. S. (2006) · Clinical Science · doi:10.1042/cs20050163 · Cited by 619 · see citing works
The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression
Chang, Q., Khare, G., Dani, V., Nelson, S., & Jaenisch, R. (2006) · Neuron · doi:10.1016/j.neuron.2005.12.027 · Cited by 578 · see citing works
Activation of Trk neurotrophin receptors in the absence of neurotrophins
Lee, F. S., & Chao, M. V. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.061020198 · Cited by 484 · see citing works
Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents
Massa, S. M., Yang, T., Xie, Y., Shi, J., Bilgen, M., Joyce, J. N., Nehama, D., Rajadas, J., & Longo, F. M. (2010) · Journal of Clinical Investigation · doi:10.1172/jci41356 · Cited by 406 · see citing works
Self-citationMecp2 Deficiency Disrupts Norepinephrine and Respiratory Systems in Mice
Viemari, J., Roux, J., Tryba, A. K., Saywell, V., Burnet, H., Peña‐Ortega, F., Zanella, S., Bévengut, M., Barthélémy-Requin, M., Herzing, L. B. K., et al. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.4373-05.2005 · Cited by 294 · see citing works
Fyffe, S. L., Neul, J. L., Samaco, R. C., Chao, H.-T., Ben-Shachar, S., Moretti, P., McGill, B. E., Goulding, E. H., Sullivan, E., Tecott, L. H., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.07.030 · Cited by 254 · see citing works
Ogier, M., Wang, H., Hong, E. J., Wang, Q., Greenberg, M. E., & Katz, D. M. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.1869-07.2007 · Cited by 246 · see citing works
Self-citationKatz, D. M., Dutschmann, M., Ramirez, J., & Hilaire, G. (2009) · Respiratory Physiology & Neurobiology · doi:10.1016/j.resp.2009.04.017 · Cited by 185 · see citing works
Self-citationExogenous Brain-Derived Neurotrophic Factor Rescues Synaptic Dysfunction inMecp2-Null Mice
Kline, D. D., Ogier, M., Kunze, D. L., & Katz, D. M. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.5503-09.2010 · Cited by 177 · see citing works
Self-citationWeese‐Mayer, D. E., Lieske, S. P., Boothby, C. M., Kenny, A. S., Bennett, H., Silvestri, J. M., & Ramirez, J. (2006) · Pediatric Research · doi:10.1203/01.pdr.0000238302.84552.d0 · Cited by 172 · see citing works
Correction of respiratory disorders in a mouse model of Rett syndrome
Abdala, A. P., Dutschmann, M., Bissonnette, J. M., & Paton, J. F. R. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1012104107 · Cited by 170 · see citing works
Rett syndrome: analysis of deaths in the British survey.
Kerr, A., Armstrong, D. D., Prescott, R. J., Doyle, D., & Kearney, D. L. (1997) · PubMed · Cited by 159 · see citing works
Wang, H., Chan, S.-A., Ogier, M., Hellard, D., Wang, Q., Smith, C., & Katz, D. M. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1810-06.2006 · Cited by 156 · see citing works
Self-citationDistinctive features of Trk neurotrophin receptor transactivation by G protein-coupled receptors
Lee, F. S., Rajagopal, R., & Chao, M. V. (2002) · Cytokine & Growth Factor Reviews · doi:10.1016/s1359-6101(01)00024-7 · Cited by 146 · see citing works
Deng, V., Matagne, V., Banine, F., Frerking, M. E., Ohliger-Frerking, P., Budden, S. S., Pevsner, J., Dissen, G. A., Sherman, L. S., & Ojeda, S. R. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm007 · Cited by 146 · see citing works
Thoby‐Brisson, M., Cauli, B., Champagnat, J., Fortin, G., & Katz, D. M. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-20-07685.2003 · Cited by 102 · see citing works
Self-citationThe substrates of memory: Defects, treatments, and enhancement
LYNCH, G. S., Rex, C. S., Chen, L. Y., & Gall, C. M. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2007.11.082 · Cited by 102 · see citing works
Bałkowiec, A., Kunze, D. L., & Katz, D. M. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-05-01904.2000 · Cited by 98 · see citing works
Self-citationOral treatment with desipramine improves breathing and life span in Rett syndrome mouse model
Zanella, S., Mebarek, S., Lajard, A.-M., Picard, N., Dutschmann, M., & Hilaire, G. (2007) · Respiratory Physiology & Neurobiology · doi:10.1016/j.resp.2007.08.009 · Cited by 89 · see citing works
MeCP2 Is Critical within HoxB1-Derived Tissues of Mice for Normal Lifespan
Ward, C. S., Arvide, E. M., Huang, T.-W., Yoo, J. W., Noebels, J. L., & Neul, J. L. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.0057-11.2011 · Cited by 87 · see citing works
CEP-1347 reduces mutant huntingtin-associated neurotoxicity and restores BDNF levels in R6/2 mice
Apostol, B. L., Simmons, D. A., Zuccato, C., Illes, K., Pallos, J., Casale, M., Conforti, P., Ramos, C., Roarke, M., Kathuria, S., et al. (2008) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2008.04.007 · Cited by 83 · see citing works
The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome
Zeev, B. B., Bebbington, A., Ho, G., Leonard, H., de Klerk, N. H., Gak, E., Vecksler, M., & Christodoulou, J. (2009) · Neurology · doi:10.1212/01.wnl.0000345664.72220.6a · Cited by 81 · see citing works
Ogier, M., & Katz, D. M. (2008) · Respiratory Physiology & Neurobiology · doi:10.1016/j.resp.2008.04.005 · Cited by 73 · see citing works
Self-citationQian, M. D., Zhang, J., Tan, X.-Y., Wood, A., Gill, D., & Cho, S. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1118-06.2006 · Cited by 67 · see citing works
Yang, T., Bernabeu, R., Xie, Y., Zhang, J. S., Massa, S. M., Rempel, H. C., & Longo, F. M. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-08-03353.2003 · Cited by 55 · see citing works
Self-citationAdult reversal of cognitive phenotypes in neurodevelopmental disorders
Silva, A. J., & Ehninger, D. (2009) · Journal of Neurodevelopmental Disorders · doi:10.1007/s11689-009-9018-7 · Cited by 44 · see citing works
Rigamonti, D., Bolognini, D., Mutti, C., Zuccato, C., Tartari, M., Sola, F., Valenza, M., Kazantsev, A. G., & Cattaneo, E. F. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m609885200 · Cited by 43 · see citing works
Neurotrophin small-molecule mimetics
Me, Y., & Longo, F. M. (2000) · Progress in brain research · doi:10.1016/s0079-6123(00)28030-8 · Cited by 40 · see citing works
Self-citationBissonnette, J. M., & Knopp, S. J. (2007) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00843.2007 · Cited by 33 · see citing works
Kron, M., Reuter, J., Gerhardt, E., Manzke, T., Zhang, W., & Dutschmann, M. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2007.148916 · Cited by 32 · see citing works
Kron, M., Zhang, W., & Dutschmann, M. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05960.x · Cited by 26 · see citing works
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Levy, M. J. F., Boulle, F., Steinbusch, H. W., van den Hove, D. L. A., Kenis, G., & Lanfumey, L. (2018) · Psychopharmacology · doi:10.1007/s00213-018-4950-4 · Cited by 308 · see citing works
Preclinical research in Rett syndrome: setting the foundation for translational success
Katz, D. M., Berger-Sweeney, J. E., Eubanks, J. H., Justice, M. J., Neul, J. L., Pozzo-Miller, L., Blue, M. E., Christian, D., Crawley, J. N., Giustetto, M., et al. (2012) · Disease Models & Mechanisms · doi:10.1242/dmm.011007 · Cited by 206 · see citing works
Self-citationMolecular mechanisms of brain-derived neurotrophic factor in neuro-protection: Recent developments
Zhao, H., Alam, A., San, C.-Y., Eguchi, S., Chen, Q., Lian, Q., & Ma, D. (2017) · Brain Research · doi:10.1016/j.brainres.2017.03.029 · Cited by 122 · see citing works
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Boltaev, U., Meyer, Y., Tolibzoda, F., Jacques, T., Gassaway, M., Xu, Q., Wagner, F., Zhang, Y.-L., Palmer, M., Holson, E., et al. (2017) · Science Signaling · doi:10.1126/scisignal.aal1670 · Cited by 94 · see citing works
Warnault, V., Darcq, E., Morisot, N., Phamluong, K., Wilbrecht, L., Massa, S. M., Longo, F. M., & Ron, D. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.06.007 · Cited by 89 · see citing works
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Kishi, N., MacDonald, J. L., Ye, J., Molyneaux, B. J., Azim, E., & Macklis, J. D. (2016) · Nature Communications · doi:10.1038/ncomms10520 · Cited by 69 · see citing works
Nomura, T., Musial, T. F., Marshall, J. J., Zhu, Y., Remmers, C. L., Xu, J., Nicholson, D. A., & Contractor, A. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.2893-16.2017 · Cited by 64 · see citing works
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- Authors
- Schmid, D. A., Yang, T., Ogier, M., Adams, I., Mirakhur, Y., Wang, Q., Massa, S. M., Longo, F. M., & Katz, D. M.
- Affiliations
- Case Western Reserve University (US)
- Stanford Medicine (US)
- San Francisco VA Medical Center (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-02-01
- Volume
- 32
- Issue
- 5
- Pages
- 1803-1810
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3710112
- OpenAlex
- W2043690181
- Cited by
- 152
- References
- 41
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 8 · 2023: 7 · 2022: 5 · 2021: 7 · 2020: 9 · 2019: 9 · 2018: 12 · 2017: 9 · 2016: 14 · 2015: 11 · 2014: 18 · 2013: 20 · 2012: 12
- FWCI
- 11.72
- 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
- U.S. Department of Veterans Affairs
- Koret Foundation
- International Rett Syndrome Foundation
- Office of Research and Development
- Jean Perkins Foundation
- National Institute of Neurological Disorders and Stroke (R01NS057398)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- Rett syndrome, TrkB receptor, BDNF signaling, MeCP2, respiratory dysfunction, tachypnea, apnea, medulla, passive optical networks, therapeutic target
- MeSH terms
- Animals, Benzamides, Disease Models, Animal, Female, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Phosphorylation, Rett Syndrome, Respiratory Mechanics, Mice, Knockout, Receptor, trkB, Mice, Methyl-CpG-Binding Protein 2, Drug Partial Agonism, Mice, 129 Strain
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