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Interplay between brain BDNF and glutamatergic systems: A brief state of the evidence and association with the pathogenesis of depression

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Abstract

The excitatory neurotransmitter glutamate system and the brain-derived neurotrophic factor (BDNF) system are principally involved in phenomena of cellular and synaptic plasticity. These systems are interacting, and disclosing mechanisms of such interactions is critically important for understanding the machinery of neuroplasticity and its modulation in normal and pathological situations. The short state of evidence in this review addresses experimentally confirmed connections of these mechanisms and their potential relation to the pathogenesis of depression. The connections between the two systems are numerous and bidirectional, providing for mutual regulation of the glutamatergic and BDNF systems. The available data suggest that it is complex and well-coordinating nature of these connections that secures optimal synaptic and cellular plasticity in the normal brain. Both systems are associated with the pathogenesis of depression, and the disturbance of tight and well-balanced associations between them results in unfavorable changes in neuronal plasticity underlying depressive disorders and other mood diseases.

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Abbreviations

AMPAR:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors

BDNF:

brain-derived neurotrophic factor

LTP:

long-term potentiation

NMDAR:

Nmethyl-D-aspartate receptors

p75 (NTR):

a low-affinity nerve growth factor receptor

TrkB:

type B tyrosine kinase receptor for BDNF

References

  1. Rothman, S. M., and Mattson, M. P. (2013) Activitydependent, stress-responsive BDNF signaling and the quest for optimal brain health and resilience throughout the lifespan, Neuroscience, 239, 228–240.

    Article  CAS  PubMed  Google Scholar 

  2. Mattson, M. P. (2008) Glutamate and neurotrophic factors in neuronal plasticity and disease, Ann. N. Y. Acad. Sci., 1144, 97–112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Jarvis, C. R., Xiong, Z. G., Plant, J. R., Churchill, D., Lu, W. Y., MacVicar, B. A., and MacDonald, J. F. (1997) Neurotrophin modulation of NMDA receptors in cultured murine and isolated rat neurons, J. Neurophysiol., 78, 2363–2371.

    CAS  PubMed  Google Scholar 

  4. Song, D. K., Choe, B., Bae, J. H., Park, W. K., Han, I. S., Ho, W. K., and Earm, Y. E. (1998) Brain-derived neurotrophic factor rapidly potentiates synaptic transmission through NMDA, but suppresses it through non-NMDA receptors in rat hippocampal neuron, Brain Res., 799, 176–179.

    Article  CAS  PubMed  Google Scholar 

  5. Lessmann, V., and Heumann, R. (1998) Modulation of unitary glutamatergic synapses by neurotrophin-4/5 or brain-derived neurotrophic factor in hippocampal microcultures: presynaptic enhancement depends on pre-established paired-pulse facilitation, Neuroscience, 86, 399–413.

    Article  CAS  PubMed  Google Scholar 

  6. Kolb, J. E., Trettel, J., and Levine, E. S. (2005) BDNF enhancement of postsynaptic NMDA receptors is blocked by ethanol, Synapse, 55, 52–57.

    Article  CAS  PubMed  Google Scholar 

  7. Lyons, M. R., Chen, L. F., Deng, J. V., Finn, C., Pfenning, A., Sabhlok, A., Wilson, K., and West, A. E. (2016) The transcription factor calcium-response factor limits NMDA receptor-dependent transcription in the developing brain, J. Neurochem., 137, 164–176.

    Article  CAS  PubMed  Google Scholar 

  8. Wu, K., Len, G. W., McAuliffe, G., Ma, C., Tai, J. P., Xu, F., and Black, I. B. (2004) Brain-derived neurotrophic factor acutely enhances tyrosine phosphorylation of the AMPA receptor subunit GluR1 via NMDA receptor-dependent mechanisms, Brain. Res. Mol. Brain Res., 130, 178–186.

    Article  CAS  PubMed  Google Scholar 

  9. O’Neill, M. J., Bleakman, D., Zimmerman, D. M., and Nisenbaum, E. S. (2004) AMPA receptor potentiators for the treatment of CNS disorders, Curr. Drug Targets CNS Neurol. Disord., 3, 181–194.

    Article  PubMed  Google Scholar 

  10. Jourdi, H., Iwakura, Y., Narisawa-Saito, M., Ibaraki, K., Xiong, H., Watanabe, M., Hayashi, Y., Takei, N., and Nawa, H. (2003) Brain-derived neurotrophic factor signal enhances and maintains the expression of AMPA receptorassociated PDZ proteins in developing cortical neurons, Dev. Biol., 263, 216–230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lauterborn, J. C., Pineda, E., Chen, L. Y., Ramirez, E. A., Lynch, G., and Gall, C. M. (2009) Ampakines cause sustained increases in brain-derived neurotrophic factor signaling at excitatory synapses without changes in AMPA receptor subunit expression, Neuroscience, 159, 283–295.

    Article  CAS  PubMed  Google Scholar 

  12. Briz, V., Liu, Y., Zhu, G., Bi, X., and Baudry, M. (2015) A novel form of synaptic plasticity in field CA3 of hippocampus requires GPER1 activation and BDNF release, J. Cell. Biol., 210, 1225–1237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Luscher, C., and Malenka, R. C. (2012) NMDA receptordependent long-term potentiation and long-term depression (LTP/LTD), Cold Spring Harb. Perspect. Biol., 4, pii: a005710.

  14. Lu, H., Park, H., and Poo, M. M. (2013) Spike-timingdependent BDNF secretion and synaptic plasticity, Philos. Trans. R. Soc. Lond. B Biol. Sci., 369, 20130132.

    Article  PubMed  Google Scholar 

  15. Leal, G., Afonso, P. M., Salazar, I. L., and Duarte, C. B. (2015) Regulation of hippocampal synaptic plasticity by BDNF, Brain Res., 1621, 82–101.

    Article  CAS  PubMed  Google Scholar 

  16. Ninan, I., Bath, K. G., Dagar, K., Perez-Castro, R., Plummer, M. R., Lee, F. S., and Chao, M. V. (2010) The BDNF Val66Met polymorphism impairs NMDA receptordependent synaptic plasticity in the hippocampus, J. Neurosci., 26, 8866–8870.

    Article  Google Scholar 

  17. Jing, D., Lee, F. S., and Ninan, I. (2016) The BDNF Val66Met polymorphism enhances glutamatergic transmission but diminishes activity-dependent synaptic plasticity in the dorsolateral striatum, Neuropharmacology, pii: S0028–3908(16)30283–0.

    Google Scholar 

  18. Nasca, C., Zelli, D., Bigio, B., Piccinin, S., Scaccianoce, S., Nistico, R., and McEwen, B. S. (2015) Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity, Proc. Natl. Acad. Sci. USA, 112, 4960–4965.

    Article  Google Scholar 

  19. Lu, B., Nagappan, G., and Lu, Y. (2014) BDNF and synaptic plasticity, cognitive function, and dysfunction, Handbook Exp. Pharmacol., 220, 223–250.

    Article  CAS  Google Scholar 

  20. Thompson, R. M., Weickert, C. S., Wyatt, E., and Webster, M. J. (2011) Decreased BDNF, trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders, J. Psychiatry Neurosci., 36, 195–203.

    Article  Google Scholar 

  21. Carvalho, A. L., Caldeira, M. V., Santos, S. D., and Duarte, C. B. (2008) Role of the brain-derived neurotrophic factor at glutamatergic synapses, Br. J. Pharmacol., 153, S310–324.

    Article  CAS  PubMed  Google Scholar 

  22. Chang, L. C., Jamain, S., Lin, C. W., Rujescu, D., Tseng, G. C., and Sibille, E. (2014) A conserved BDNF, glutamateand GABA-enriched gene module related to human depression identified by coexpression meta-analysis and DNA variant genome-wide association studies, PLoS One, 9, e90980.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Martinez-Turrillas, R., Del Rio, J., and Frechilla, D. (2005) Sequential changes in BDNF mRNA expression and synaptic levels of AMPA receptor subunits in rat hippocampus after chronic antidepressant treatment, Neuropharmacology, 49, 1178–1188.

    Article  CAS  PubMed  Google Scholar 

  24. Legutko, B., Szewczyk, B., Pomierny-Chamiolo, L., Nowak, G., and Pilc, A. (2006) Effect of MPEP treatment on brain-derived neurotrophic factor gene expression, Pharmacol. Rep., 58, 427–430.

    CAS  PubMed  Google Scholar 

  25. Gulyaeva, N. V. (2016) Studies on stress-induced modulation of long-term potentiation in rodent hippocampus: what can we learn about pathogenesis of depression? Translat. Brain Rhythm., 1, doi: 10.15761/TBR.1000107.

    Google Scholar 

  26. Lindholm, J. S., Autio, H., Vesa, L., Antila, H., Lindemann, L., Hoener, M. C., Skolnick, P., Rantamaki, T., and Castren, E. (2012) The antidepressant-like effects of glutamatergic drugs ketamine and AMPA receptor potentiator LY451646 are preserved in bdnf+/-heterozygous null mice, Neuropharmacology, 62, 391–397.

    Article  CAS  PubMed  Google Scholar 

  27. Liu, W. X., Wang, J., Xie, Z. M., Xu, N., Zhang, G. F., Jia, M., Zhou, Z. Q., Hashimoto, K., and Yang, J. J. (2016) Regulation of glutamate transporter 1 via BDNF-TrkB signaling plays a role in the anti-apoptotic and antidepressant effects of ketamine in chronic unpredictable stress model of depression, Psychopharmacology (Berl.), 233, 405–415.

    Article  CAS  Google Scholar 

  28. Jia, N., Li, Q., Sun, H., Song, Q., Tang, G., Sun, Q., Wang, W., Chen, R., Li, H., and Zhu, Z. (2015) Alterations of group I mGluRs and BDNF associated with behavioral abnormity in prenatally stressed offspring rats, Neurochem. Res., 40, 1074–1082.

    Article  CAS  PubMed  Google Scholar 

  29. Numakawa, T., Kumamaru, E., Adachi, N., Yagasaki, Y., Izumi, A., and Kunugi, H. (2009) Glucocorticoid receptor interaction with TrkB promotes BDNF-triggered PLCgamma signaling for glutamate release via a glutamate transporter, Proc. Natl. Acad. Sci. USA, 106, 647–652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Vasquez, C. E., Riener, R., Reynolds, E., and Britton, G. B. (2014) NMDA receptor dysregulation in chronic state: a possible mechanism underlying depression with BDNF downregulation, Neurochem. Int., 79, 88–97.

    Article  CAS  PubMed  Google Scholar 

  31. Alt, A., Nisenbaum, E. S., Bleakman, D., and Witkin, J. M. (2006) A role for AMPA receptors in mood disorders, Biochem. Pharmacol., 71, 1273–1288.

    Article  CAS  PubMed  Google Scholar 

  32. Koike, H., Fukumoto, K., Iijima, M., and Chaki, S. (2013) Role of BDNF/TrkB signaling in antidepressant-like effects of a group II metabotropic glutamate receptor antagonist in animal models of depression, Behav. Brain Res., 238, 48–52.

    Article  CAS  PubMed  Google Scholar 

  33. Liu, C. Y., Jiang, X. X., Zhu, Y. H., and Wei, D. N. (2012) Metabotropic glutamate receptor 5 antagonist 2-methyl-6(phenylethynyl)pyridine produces antidepressant effects in rats: role of brain-derived neurotrophic factor, Neuroscience, 223, 219–224.

    Article  CAS  PubMed  Google Scholar 

  34. Henderson, T. A. (2016) Practical application of the neuroregenerative properties of ketamine: real world treatment experience, Neural Regen. Res., 11, 195–200.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kim, H. K., Nunes, P. V., Oliveira, K. C., Young, L. T., and Lafer, B. (2016) Neuropathological relationship between major depression and dementia: a hypothetical model and review, Prog. Neuropsychopharmacol. Biol. Psychiatry, 67, 51–57.

    Article  PubMed  Google Scholar 

  36. Kim, Y. K., and Na, K. S. (2016) Role of glutamate receptors and glial cells in the pathophysiology of treatmentresistant depression, Prog. Neuropsychopharmacol. Biol. Psychiatry, 70, 117–126.

    Article  CAS  PubMed  Google Scholar 

  37. Whleb, E. S., Gerhard, D., Thomas, A., and Duman, R. S. (2016) Molecular and cellular mechanisms of rapid-acting antidepressants ketamine and scopolamine, Curr. Neuropharmacol., Mar. 8.

    Google Scholar 

  38. Browne, C. A., and Lucki, I. (2013) Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants, Front. Pharmacol., 4, doi: 10.3389/fphar. 2013.00161.

    Google Scholar 

  39. Monteggia, L. M., Gideons, E., and Kavalali, E. T. (2013) The role of eukaryotic elongation factor 2 kinase in rapid antidepressant action of ketamine, Biol. Psychiatry, 73, 1199–1203.

    Article  CAS  PubMed  Google Scholar 

  40. Bjorkholm, C., and Monteggia, L. M. (2015) BDNF–a key transducer of antidepressant effects, Neuropharmacology, 102, 72–79.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Scheuing, L., Chiu, C. T., Liao, H. M., and Chuang, D. M. (2015) Antidepressant mechanism of ketamine: perspective from preclinical studies, Front. Neurosci., 9, doi: 10.3389/fnins.2015.00249.

    Google Scholar 

  42. Lepack, A. E., Fuchikami, M., Dwyer, J. M., Banasr, M., and Duman, R. S. (2014) BDNF release is required for the behavioral actions of ketamine, Int. J. Neuropsychopharmacol., 18, doi: 10.1093/ijnp/pyu033.

    Google Scholar 

  43. Pochwat, B., Sowa-Kucma, M., Kotarska, K., Misztak, P., Nowak, G., and Szewczyk, B. (2015) Antidepressant-like activity of magnesium in the olfactory bulbectomy model is associated with the AMPA/BDNF pathway, Psychopharmacology (Berl.), 232, 355–367.

    Article  CAS  Google Scholar 

  44. Duman, R. S. (2014) Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections, Dialogues Clin. Neurosci., 16, 11–27.

    PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485, Moscow, Russia

    N. V. Gulyaeva

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Correspondence to N. V. Gulyaeva.

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Published in Russian in Biokhimiya, 2017, Vol. 82, No. 3, pp. 441-448.

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Gulyaeva, N.V. Interplay between brain BDNF and glutamatergic systems: A brief state of the evidence and association with the pathogenesis of depression. Biochemistry Moscow 82, 301–307 (2017). https://doi.org/10.1134/S0006297917030087

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  • DOI: https://doi.org/10.1134/S0006297917030087

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