Increased brain-derived neurotrophic factor (BDNF) protein concentrations in mice lacking brain serotonin

  • Golo Kronenberg
  • Valentina Mosienko
  • Karen Gertz
  • Natalia Alenina
  • Rainer Hellweg
  • Friederike KlempinEmail author
Short Communication


The interplay between BDNF signaling and the serotonergic system remains incompletely understood. Using a highly sensitive enzyme-linked immunosorbent assay, we studied BDNF concentrations in hippocampus and cortex of two mouse models of altered serotonin signaling: tryptophan hydroxylase (Tph)2-deficient (Tph2 /) mice lacking brain serotonin and serotonin transporter (SERT)-deficient (SERT−/−) mice lacking serotonin re-uptake. Surprisingly, hippocampal BDNF was significantly elevated in Tph2 / mice, whereas no significant changes were observed in SERT−/− mice. Furthermore, BDNF levels were increased in the prefrontal cortex of Tph2 / but not of SERT−/− mice. Our results emphasize the interaction between serotonin signaling and BDNF. Complete lack of brain serotonin induces BDNF expression.


BDNF SERT TPH2 Serotonin Depression Antidepressant 



This work was supported by the Bundesministerium für Bildung und Forschung (Center for Stroke Research Berlin to K.G. and G.K.) and DFG Grant KL 2805/1-1 to F.K. We would like to thank Thorsten Riepenhausen, Silvia Saft, and Sabine Grueger for excellent technical support.

Conflict of interest



  1. 1.
    Walther DJ et al (2003) Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299(5603):76CrossRefPubMedGoogle Scholar
  2. 2.
    Descarries L, Riad M (2012) Effects of the antidepressant fluoxetine on the subcellular localization of 5-HT1A receptors and SERT. Philos Trans R Soc Lond B Biol Sci 367(1601):2416–2425CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Murphy DL, Lesch KP (2008) Targeting the murine serotonin transporter: insights into human neurobiology. Nat Rev Neurosci 9(2):85–96CrossRefPubMedGoogle Scholar
  4. 4.
    Haubensak W et al (1998) BDNF–GFP containing secretory granules are localized in the vicinity of synaptic junctions of cultured cortical neurons. J Cell Sci 111(Pt 11):1483–1493PubMedGoogle Scholar
  5. 5.
    Altar CA, DiStefano PS (1998) Neurotrophin trafficking by anterograde transport. Trends Neurosci 21(10):433–437CrossRefPubMedGoogle Scholar
  6. 6.
    Ferres-Coy A et al (2013) RNAi-mediated serotonin transporter suppression rapidly increases serotonergic neurotransmission and hippocampal neurogenesis. Transl Psychiatry 3:e211CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Mattson MP, Maudsley S, Martin B (2004) BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci 27(10):589–594CrossRefPubMedGoogle Scholar
  8. 8.
    Gass P, Riva MA (2007) CREB, neurogenesis and depression. BioEssays 29(10):957–961CrossRefPubMedGoogle Scholar
  9. 9.
    Nibuya M, Morinobu S, Duman RS (1995) Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15(11):7539–7547PubMedGoogle Scholar
  10. 10.
    Nibuya M, Nestler EJ, Duman RS (1996) Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 16(7):2365–2372PubMedGoogle Scholar
  11. 11.
    Benmansour S et al (2008) Influence of brain-derived neurotrophic factor (BDNF) on serotonin neurotransmission in the hippocampus of adult rodents. Eur J Pharmacol 587(1–3):90–98CrossRefPubMedGoogle Scholar
  12. 12.
    Daftary SS, Calderon G, Rios M (2012) Essential role of brain-derived neurotrophic factor in the regulation of serotonin transmission in the basolateral amygdala. Neuroscience 224:125–134CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Urani A, Chourbaji S, Gass P (2005) Mutant mouse models of depression: candidate genes and current mouse lines. Neurosci Biobehav Rev 29(4–5):805–828CrossRefPubMedGoogle Scholar
  14. 14.
    Mosienko V, Beis D, Pasqualetti M, Waider J, Matthes S, Qadri F, Bader M, Alenina N (2015) Life without brain serotonin: reevaluation of serotonin function with mice deficient in brain serotonin synthesis. Behav Brain Res 277:78–88CrossRefPubMedGoogle Scholar
  15. 15.
    Bengel D et al (1998) Altered brain serotonin homeostasis and locomotor insensitivity to 3,4-methylenedioxymethamphetamine (“Ecstasy”) in serotonin transporter-deficient mice. Mol Pharmacol 53(4):649–655PubMedGoogle Scholar
  16. 16.
    Kim DK et al (2005) Altered serotonin synthesis, turnover and dynamic regulation in multiple brain regions of mice lacking the serotonin transporter. Neuropharmacology 49(6):798–810CrossRefPubMedGoogle Scholar
  17. 17.
    Shen HW et al (2004) Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters. Neuropsychopharmacology 29(10):1790–1799CrossRefPubMedGoogle Scholar
  18. 18.
    Malberg JE et al (2000) Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20(24):9104–9110PubMedGoogle Scholar
  19. 19.
    Alenina N, Klempin F (2015) The role of serotonin in adult hippocampal neurogenesis. Behav Brain Res 277:49–57CrossRefPubMedGoogle Scholar
  20. 20.
    Alenina N et al (2009) Growth retardation and altered autonomic control in mice lacking brain serotonin. Proc Natl Acad Sci USA 106(25):10332–10337CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Mosienko V et al (2012) Exaggerated aggression and decreased anxiety in mice deficient in brain serotonin. Transl Psychiatry 2:e122CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Hellweg R et al (2007) Olfactory bulbectomy in mice leads to increased BDNF levels and decreased serotonin turnover in depression-related brain areas. Neurobiol Dis 25(1):1–7CrossRefPubMedGoogle Scholar
  23. 23.
    Hellweg R et al (2006) Spatial navigation in complex and radial mazes in APP23 animals and neurotrophin signaling as a biological marker of early impairment. Learn Mem 13(1):63–71CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Hellweg R et al (2003) Neuroprotection and neuronal dysfunction upon repetitive inhibition of oxidative phosphorylation. Exp Neurol 183(2):346–354CrossRefPubMedGoogle Scholar
  25. 25.
    Chourbaji S et al (2012) The impact of environmental enrichment on sex-specific neurochemical circuitries—effects on brain-derived neurotrophic factor and the serotonergic system. Neuroscience 220:267–276CrossRefPubMedGoogle Scholar
  26. 26.
    Pollock GS et al (2001) Effects of early visual experience and diurnal rhythms on BDNF mRNA and protein levels in the visual system, hippocampus, and cerebellum. J Neurosci 21(11):3923–3931PubMedGoogle Scholar
  27. 27.
    Fukuchi M, Tsuda M (2010) Involvement of the 3′-untranslated region of the brain-derived neurotrophic factor gene in activity-dependent mRNA stabilization. J Neurochem 115(5):1222–1233CrossRefPubMedGoogle Scholar
  28. 28.
    West AE, Pruunsild P, Timmusk T (2014) Neurotrophins: transcription and translation. Handb Exp Pharmacol 220:67–100CrossRefPubMedGoogle Scholar
  29. 29.
    Migliarini S, Pacini G, Pelosi B, Lunardi G, Pasqualetti M (2013) Lack of brain serotonin affects postnatal development and serotonergic neuronal circuitry formation. Mol Psychiatry 18(10):1106–1118CrossRefPubMedGoogle Scholar
  30. 30.
    Zhang X et al (2005) Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45(1):11–16CrossRefPubMedGoogle Scholar
  31. 31.
    Halpin LE, Collins SA, Yamamoto BK (2014) Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine. Life Sci 97(1):37–44CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Molendijk ML et al (2011) Serum levels of brain-derived neurotrophic factor in major depressive disorder: state-trait issues, clinical features and pharmacological treatment. Mol Psychiatry 16(11):1088–1095CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Carola V et al (2008) Identifying molecular substrates in a mouse model of the serotonin transporter × environment risk factor for anxiety and depression. Biol Psychiatry 63(9):840–846CrossRefPubMedGoogle Scholar
  34. 34.
    Calabrese F et al (2015) Exposure to early life stress regulates Bdnf expression in SERT mutant rats in an anatomically selective fashion. J Neurochem 132(1):146–154CrossRefPubMedGoogle Scholar
  35. 35.
    Molteni R et al (2010) Reduced function of the serotonin transporter is associated with decreased expression of BDNF in rodents as well as in humans. Neurobiol Dis 37(3):747–755CrossRefPubMedGoogle Scholar
  36. 36.
    Szapacs ME et al (2004) Exploring the relationship between serotonin and brain-derived neurotrophic factor: analysis of BDNF protein and extraneuronal 5-HT in mice with reduced serotonin transporter or BDNF expression. J Neurosci Methods 140(1–2):81–92CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Golo Kronenberg
    • 1
  • Valentina Mosienko
    • 2
    • 4
  • Karen Gertz
    • 3
  • Natalia Alenina
    • 2
  • Rainer Hellweg
    • 1
  • Friederike Klempin
    • 2
    Email author
  1. 1.Department of Psychiatry and Psychotherapy, Campus Charité MitteCharité - University Medicine BerlinBerlinGermany
  2. 2.Research Team ‘Cardiovascular Hormones and Peptides’Max-Delbruck-Center for Molecular Medicine (MDC)BerlinGermany
  3. 3.Department of NeurologyCharité - University Medicine BerlinBerlinGermany
  4. 4.School of Physiology and PharmacologyUniversity of BristolBristolUK

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