Download PDF
Pharmacopsychiatry 2021; 54(05): 205-213
DOI: 10.1055/a-1363-1680
Original Paper

Robustly High Hippocampal BDNF levels under Acute Stress in Mice Lacking the Full-length p75 Neurotrophin Receptor

Björn H. Schott 
1   Department of Psychiatry and Psychotherapy, University Medical Center Göttingen (UMG), Göttingen, Germany
2   Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Berlin, Germany
3   Leibniz Institute for Neurobiology, Department of Behavioral Neurology, Magdeburg, Germany
4   German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
,
Golo Kronenberg
2   Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Berlin, Germany
5   University of Leicester and Leicestershire Partnership NHS Trust, Leicester, United Kingdom
,
Ulrike Schmidt
1   Department of Psychiatry and Psychotherapy, University Medical Center Göttingen (UMG), Göttingen, Germany
6   Department of Psychiatry and Psychotherapy, University Medical Center Bonn, Bonn, Germany
,
Henning P. Düsedau
7   Institute of Inflammation and Neurodegeneration, Otto von Guericke University, Magdeburg, Germany
,
Stefanie Ehrentraut
7   Institute of Inflammation and Neurodegeneration, Otto von Guericke University, Magdeburg, Germany
,
Olga Geisel
2   Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Berlin, Germany
,
Oliver von Bohlen und Halbach
8   Institute of Anatomy and Cell Biology, Universitätsmedizin Greifswald, Greifswald, Germany
,
Peter Gass
9   Central Institute for Mental Health, Department of Psychiatry and Psychotherapy, Heidelberg University, Mannheim Faculty, Germany
,
Ildiko Rita Dunay‡
7   Institute of Inflammation and Neurodegeneration, Otto von Guericke University, Magdeburg, Germany
,
Rainer Hellweg‡
2   Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Berlin, Germany
› Author Affiliations Funding This work was supported by the Deutsche Forschungsgemeinschaft (SFB 779, TP A08, to B.H.S., SFB 854, TP25, to I.R.D., and DFG KR 2591/6–1 to G.K.), and by the State of Saxony-Anhalt and the European Union (Research Alliance “Autonomy in Old Age” to B.H.S. and I.R.D.). The funding agencies had no role in the design, conduction, or interpretation of this work.
› Further Information
Also available at
    Permissions and Reprints

ABSTRACT

Background Brain-derived neurotrophic factor (BDNF) exerts its effects on neural plasticity via 2 distinct receptor types, the tyrosine kinase TrkB and the p75 neurotrophin receptor (p75NTR). The latter can promote inflammation and cell death while TrkB is critically involved in plasticity and memory, particularly in the hippocampus. Acute and chronic stress have been associated with suppression of hippocampal BDNF expression and impaired hippocampal plasticity. We hypothesized that p75NTR might be involved in the hippocampal stress response, in particular in stress-induced BDNF suppression, which might be accompanied by increased neuroinflammation.

Method We assessed hippocampal BDNF protein concentrations in wild-type mice compared that in mice lacking the long form of the p75NTR (p75NTRExIII−/−) with or without prior exposure to a 1-hour restraint stress challenge. Hippocampal BDNF concentrations were measured using an optimized ELISA. Furthermore, whole-brain mRNA expression of pro-inflammatory interleukin-6 (Il6) was assessed with RT-PCR.

Results Deletion of full-length p75NTR was associated with higher hippocampal BDNF protein concentration in the stress condition, suggesting persistently high hippocampal BDNF levels in p75NTR-deficient mice, even under stress. Stress elicited increased whole-brain Il6 mRNA expression irrespective of genotype; however, p75NTRExIII−/− mice showed elevated baseline Il6 expression and thus a lower relative increase.

Conclusions Our results provide evidence for a role of p75NTR signaling in the regulation of hippocampal BDNF levels, particularly under stress. Furthermore, p75NTR signaling modulates baseline but not stress-related Il6 gene expression in mice. Our findings implicate p75NTR signaling as a potential pathomechanism in BDNF-dependent modulation of risk for neuropsychiatric disorders.

Key words

brain-derived neurotrophic factor - BDNF - interleukin 6 - IL-6 - p75NTR - stress - hippocampus


Publication History

Received: 27 May 2020
Received: 30 December 2020

Accepted: 12 January 2021

Article published online:
16 February 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Squire LR, Stark CE, Clark RE. The medial temporal lobe. Annu Rev Neurosci 2004; 27: 279-306
    CrossrefPubMedGoogle Scholar
  • 2 Chao MV, Lee FS. Neurotrophin survival signaling mechanisms. J Alzheimers Dis 2004; 6: S7-S11
    CrossrefPubMedGoogle Scholar
  • 3 Chourbaji S, Hortnagl H, Molteni R. et al. The impact of environmental enrichment on sex-specific neurochemical circuitries—effects on brain-derived neurotrophic factor and the serotonergic system. Neuroscience 2012; 220: 267-276
    CrossrefPubMedGoogle Scholar
  • 4 Egan MF, Kojima M, Callicott JH. et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003; 112: 257-269
    CrossrefPubMedGoogle Scholar
  • 5 von Bohlen und Halbach O, Minichiello L, Unsicker K. TrkB but not trkC receptors are necessary for postnatal maintenance of hippocampal spines. Neurobiol Aging 2008; 29: 1247-1255
    CrossrefPubMedGoogle Scholar
  • 6 Zorner B, Wolfer DP, Brandis D. et al. Forebrain-specific trkB-receptor knockout mice: behaviorally more hyperactive than “depressive. Biol Psychiatry 2003; 54: 972-982
    CrossrefPubMedGoogle Scholar
  • 7 Gentry JJ, Barker PA, Carter BD. The p75 neurotrophin receptor: Multiple interactors and numerous functions. Prog Brain Res 2004; 146: 25-39
    CrossrefPubMedGoogle Scholar
  • 8 Lee KF, Li E, Huber LJ. et al. Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 1992; 69: 737-749
    CrossrefPubMedGoogle Scholar
  • 9 Meeker R, Williams K. Dynamic nature of the p75 neurotrophin receptor in response to injury and disease. J Neuroimmune Pharmacol 2014; 9: 615-628
    CrossrefPubMedGoogle Scholar
  • 10 Düsedau HP, Kleveman J, Figueiredo CA. et al. p75(NTR) regulates brain mononuclear cell function and neuronal structure in Toxoplasma infection-induced neuroinflammation. Glia 2019; 67: 193-211
    CrossrefPubMedGoogle Scholar
  • 11 Woon FL, Sood S, Hedges DW. Hippocampal volume deficits associated with exposure to psychological trauma and posttraumatic stress disorder in adults: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 1181-1188
    CrossrefPubMedGoogle Scholar
  • 12 Schmidt U, Buell DR, Ionescu IA. et al. A role for synapsin in FKBP51 modulation of stress responsiveness: convergent evidence from animal and human studies. Psychoneuroendocrinology 2015; 52: 43-58
    CrossrefPubMedGoogle Scholar
  • 13 Herrmann L, Ionescu IA, Henes K. et al. Long-lasting hippocampal synaptic protein loss in a mouse model of posttraumatic stress disorder. PLoS One 2012; 7: e42603
    CrossrefPubMedGoogle Scholar
  • 14 Bennett MR, Lagopoulos J. Stress and trauma: BDNF control of dendritic-spine formation and regression. Prog Neurobiol 2014; 112: 80-99
    CrossrefPubMedGoogle Scholar
  • 15 Ieraci A, Mallei A, Musazzi L. et al. Physical exercise and acute restraint stress differentially modulate hippocampal brain-derived neurotrophic factor transcripts and epigenetic mechanisms in mice. Hippocampus 2015; 25: 1380-1392
    CrossrefPubMedGoogle Scholar
  • 16 Uwaya A, Lee H, Park J. et al. Acute immobilization stress following contextual fear conditioning reduces fear memory: Timing is essential. Behav Brain Funct 2016; 12: 8
    CrossrefPubMedGoogle Scholar
  • 17 Domingues M, Casaril AM, Birmann PT. et al. Effects of a selanylimidazopyridine on the acute restraint stress-induced depressive- and anxiety-like behaviors and biological changes in mice. Behav Brain Res 2019; 366: 96-107
    CrossrefPubMedGoogle Scholar
  • 18 Marmigere F, Givalois L, Rage F. et al. Rapid induction of BDNF expression in the hippocampus during immobilization stress challenge in adult rats. Hippocampus 2003; 13: 646-655
    CrossrefPubMedGoogle Scholar
  • 19 Reus GZ, Abelaira HM, Stringari RB. et al. Memantine treatment reverses anhedonia, normalizes corticosterone levels and increases BDNF levels in the prefrontal cortex induced by chronic mild stress in rats. Metab Brain Dis 2012; 27: 175-182
    CrossrefPubMedGoogle Scholar
  • 20 Hansel A, Hong S, Camara RJ. et al. Inflammation as a psychophysiological biomarker in chronic psychosocial stress. Neurosci Biobehav Rev 2010; 35: 115-121
    CrossrefPubMedGoogle Scholar
  • 21 Rohleder N. Stimulation of systemic low-grade inflammation by psychosocial stress. Psychosom Med 2014; 76: 181-189
    CrossrefPubMedGoogle Scholar
  • 22 von Schack D, Casademunt E, Schweigreiter R. et al. Complete ablation of the neurotrophin receptor p75NTR causes defects both in the nervous and the vascular system. Nat Neurosci 2001; 4: 977-978
    CrossrefPubMedGoogle Scholar
  • 23 Poser R, Dokter M. von Bohlen Und Halbach V, et al. Impact of a deletion of the full-length and short isoform of p75NTR on cholinergic innervation and the population of postmitotic doublecortin positive cells in the dentate gyrus. Front Neuroanat 2015; 9: 63
    CrossrefPubMedGoogle Scholar
  • 24 Busch R, Baldus M, Vogt MA. et al. Effects of p75NTR deficiency on cholinergic innervation of the amygdala and anxiety-like behavior. J Neurochem 2017; 141: 461-471
    CrossrefPubMedGoogle Scholar
  • 25 Kilkenny C, Browne WJ, Cuthill IC. et al. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 2010; 8: e1000412
    CrossrefPubMedGoogle Scholar
  • 26 Naumann T, Casademunt E, Hollerbach E. et al. Complete deletion of the neurotrophin receptor p75NTR leads to long-lasting increases in the number of basal forebrain cholinergic neurons. J Neurosci 2002; 22: 2409-2418
    CrossrefPubMedGoogle Scholar
  • 27 Chourbaji S, Hellweg R, Brandis D. et al. Mice with reduced brain-derived neurotrophic factor expression show decreased choline acetyltransferase activity, but regular brain monoamine levels and unaltered emotional behavior. Brain Res Mol Brain Res 2004; 121: 28-36
    CrossrefPubMedGoogle Scholar
  • 28 Chourbaji S, Zacher C, Sanchis-Segura C. et al. Social and structural housing conditions influence the development of a depressive-like phenotype in the learned helplessness paradigm in male mice. Behav Brain Res 2005; 164: 100-106
    CrossrefPubMedGoogle Scholar
  • 29 Molteni R, Calabrese F, Chourbaji S. et al. Depression-prone mice with reduced glucocorticoid receptor expression display an altered stress-dependent regulation of brain-derived neurotrophic factor and activity-regulated cytoskeleton-associated protein. J Psychopharmacol 2010; 24: 595-603
    CrossrefPubMedGoogle Scholar
  • 30 Hellweg R, Lohmann P, Huber R. et al. Spatial navigation in complex and radial mazes in APP23 animals and neurotrophin signaling as a biological marker of early impairment. Learn Mem 2006; 13: 63-71
    CrossrefPubMedGoogle Scholar
  • 31 Kronenberg G, Harms C, Sobol RW. et al. Folate deficiency induces neurodegeneration and brain dysfunction in mice lacking uracil DNA glycosylase. J Neurosci 2008; 28: 7219-7230
    CrossrefPubMedGoogle Scholar
  • 32 Hellweg R, Zueger M, Fink K. et al. Olfactory bulbectomy in mice leads to increased BDNF levels and decreased serotonin turnover in depression-related brain areas. Neurobiol Dis 2007; 25: 1-7
    CrossrefPubMedGoogle Scholar
  • 33 French T, Düsedau HP, Steffen J. et al. Neuronal impairment following chronic Toxoplasma gondii infection is aggravated by intestinal nematode challenge in an IFN-γ-dependent manner. J Neuroinflammation 2019; 16: 159
    CrossrefPubMedGoogle Scholar
  • 34 Lang D, Schott BH, van Ham M. et al. Chronic Toxoplasma infection is associated with distinct alterations in the synaptic protein composition. J Neuroinflammation 2018; 15: 216
    CrossrefPubMedGoogle Scholar
  • 35 Efron B, Tibshirani RJ. An Introduction to the Bootstrap. New York: Chapman & Hall; 1993
    CrossrefGoogle Scholar
  • 36 Elias CJ. Percentile and percentile-t bootstrap confidence intervals: a practical comparison. Journal of Econometric Methods 2015; 4: 1-9
    CrossrefPubMedGoogle Scholar
  • 37 Schott BH, Wüstenberg T, Lücke E. et al. Gradual acquisition of visuospatial associative memory representations via the dorsal precuneus. Hum Brain Mapp 2019; 40: 1554-1570
    CrossrefPubMedGoogle Scholar
  • 38 Ioannidis JP. Why most discovered true associations are inflated. Epidemiology 2008; 19: 640-648
    CrossrefPubMedGoogle Scholar
  • 39 Assmann A, Richter A, Schütze H. et al. Neurocan genome-wide psychiatric risk variant affects explicit memory performance and hippocampal function in healthy humans. Eur J Neurosci 2020; DOI: 10.1111/ejn.14872:
  • 40 Button KS, Ioannidis JP, Mokrysz C. et al. Power failure: Why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci 2013; 14: 365-376
    CrossrefPubMedGoogle Scholar
  • 41 Schulte-Herbrüggen O, Fuchs E, Abumaria N. et al. Effects of escitalopram on the regulation of brain-derived neurotrophic factor and nerve growth factor protein levels in a rat model of chronic stress. J Neurosci Res 2009; 87: 2551-2560
    CrossrefPubMedGoogle Scholar
  • 42 Nair A, Vadodaria KC, Banerjee SB. et al. Stressor-specific regulation of distinct brain-derived neurotrophic factor transcripts and cyclic AMP response element-binding protein expression in the postnatal and adult rat hippocampus. Neuropsychopharmacology 2007; 32: 1504-1519
    CrossrefPubMedGoogle Scholar
  • 43 Lippmann M, Bress A, Nemeroff CB. et al. Long-term behavioural and molecular alterations associated with maternal separation in rats. Eur J Neurosci 2007; 25: 3091-3098
    CrossrefPubMedGoogle Scholar
  • 44 Foltran RB, Diaz SL. BDNF isoforms: a round trip ticket between neurogenesis and serotonin?. J Neurochem 2016; 138: 204-221
    CrossrefPubMedGoogle Scholar
  • 45 Yasuda M, Fukuchi M, Tabuchi A. et al. Robust stimulation of TrkB induces delayed increases in BDNF and Arc mRNA expressions in cultured rat cortical neurons via distinct mechanisms. J Neurochem 2007; 103: 626-636
    CrossrefPubMedGoogle Scholar
  • 46 Esvald EE, Tuvikene J, Sirp A. et al. CREB family transcription factors are major mediators of BDNF transcriptional autoregulation in cortical neurons. J Neurosci 2020; 40: 1405-1426
    CrossrefPubMedGoogle Scholar
  • 47 Yang J, Siao CJ, Nagappan G. et al. Neuronal release of proBDNF. Nat Neurosci 2009; 12: 113-115
    CrossrefPubMedGoogle Scholar
  • 48 Gibon J, Buckley SM, Unsain N. et al. proBDNF and p75NTR control excitability and persistent firing of cortical pyramidal meurons. J Neurosci 2015; 35: 9741-9753
    CrossrefPubMedGoogle Scholar
  • 49 Jacobsen JP, Mørk A. The effect of escitalopram, desipramine, electroconvulsive seizures and lithium on brain-derived neurotrophic factor mRNA and protein expression in the rat brain and the correlation to 5-HT and 5-HIAA levels. Brain Res 2004; 1024: 183-192
    CrossrefPubMedGoogle Scholar
  • 50 Righi M, Tongiorgi E, Cattaneo A. Brain-derived neurotrophic factor (BDNF) induces dendritic targeting of BDNF and tyrosine kinase B mRNAs in hippocampal neurons through a phosphatidylinositol-3 kinase-dependent pathway. J Neurosci 2000; 20: 3165-3174
    CrossrefPubMedGoogle Scholar
  • 51 Baj G, Pinhero V, Vaghi V. et al. Signaling pathways controlling activity-dependent local translation of BDNF and their localization in dendritic arbors. J Cell Sci 2016; 129: 2852-2864
    PubMedGoogle Scholar
  • 52 Kafitz KW, Rose CR, Thoenen H. et al. Neurotrophin-evoked rapid excitation through TrkB receptors. Nature 1999; 401: 918-921
    CrossrefPubMedGoogle Scholar
  • 53 Balschun D, Wetzel W, Del Rey A. et al. Interleukin-6: A cytokine to forget. FASEB J 2004; 18: 1788-1790
    CrossrefPubMedGoogle Scholar
  • 54 Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 2011; 25: 181-213
    CrossrefPubMedGoogle Scholar
  • 55 Lima Giacobbo B, Doorduin J, Klein HC. et al. Brain-derived neurotrophic factor in brain disorders: focus on neuroinflammation. Mol Neurobiol 2018; DOI: 10.1007/s12035-018-1283-6:
  • 56 Dowling P, Ming X, Raval S. et al. Up-regulated p75NTR neurotrophin receptor on glial cells in MS plaques. Neurology 1999; 53: 1676-1682
    CrossrefPubMedGoogle Scholar
  • 57 Spitzbarth I, Cana A, Hahn K. et al. Associated occurrence of p75 neurotrophin receptor expressing aldynoglia and microglia/macrophages in long term organotypic murine brain slice cultures. Brain Res 2015; 1595: 29-42
    CrossrefPubMedGoogle Scholar
  • 58 Goshen I, Yirmiya R. Interleukin-1 (IL-1): a central regulator of stress responses. Front Neuroendocrinol 2009; 30: 30-45
    CrossrefPubMedGoogle Scholar
  • 59 Bobula B, Sowa J, Hess G. Anti-interleukin-1β antibody prevents the occurrence of repeated restraint stress-induced alterations in synaptic transmission and long-term potentiation in the rat frontal cortex. Pharmacol Rep 2015; 67: 123-128
    CrossrefPubMedGoogle Scholar
  • 60 Jangra A, Rajput P, Dwivedi DK. et al. Amelioration of repeated restraint stress-induced behavioral deficits and hippocampal anomalies with taurine treatment in mice. Neurochem Res 2020; 45: 731-740
    CrossrefPubMedGoogle Scholar
  • 61 Patterson SL. Immune dysregulation and cognitive vulnerability in the aging brain: interactions of microglia, IL-1β, BDNF and synaptic plasticity. Neuropharmacology 2015; 96: 11-18
    CrossrefPubMedGoogle Scholar
  • 62 Zhang YP, Wang HY, Zhang C. et al. Mifepristone attenuates depression-like changes induced by chronic central administration of interleukin-1β in rats. Behav Brain Res 2018; 347: 436-445
    CrossrefPubMedGoogle Scholar
  • 63 Pedraza O, Bowers D, Gilmore R. Asymmetry of the hippocampus and amygdala in MRI volumetric measurements of normal adults. J Int Neuropsychol Soc 2004; 10: 664-678
    CrossrefPubMedGoogle Scholar
  • 64 Woolard AA, Heckers S. Anatomical and functional correlates of human hippocampal volume asymmetry. Psychiatry Res 2012; 201: 48-53
    CrossrefPubMedGoogle Scholar
  • 65 Schott BH, Wüstenberg T, Wimber M. et al. The relationship between level of processing and hippocampal-cortical functional connectivity during episodic memory formation in humans. Hum Brain Mapp 2013; 34: 407-424
    CrossrefPubMedGoogle Scholar
  • 66 Velichkovsky BM, Krotkova OA, Kotov AA. et al. Consciousness in a multilevel architecture: Evidence from the right side of the brain. Conscious Cogn 2018; 64: 227-239
    CrossrefPubMedGoogle Scholar
  • 67 Raftogianni A, Stamatakis A, Papadopoulou A. et al. Effects of an early experience of reward through maternal contact or its denial on laterality of protein expression in the developing rat hippocampus. PLoS One 2012; 7: e48337
    CrossrefPubMedGoogle Scholar
  • 68 Miskolczi C, Halasz J, Mikics E. Changes in neuroplasticity following early-life social adversities: the possible role of brain-derived neurotrophic factor. Pediatr Res 2019; 85: 225-233 doi:10.1038/s41390-018-0205-7
    CrossrefPubMedGoogle Scholar
  • 69 Ornell F, Hansen F, Schuch FB. et al. Brain-derived neurotrophic factor in substance use disorders: A systematic review and meta-analysis. Drug Alcohol Depend 2018; 193: 91-103
    CrossrefPubMedGoogle Scholar
  • 70 Mojtabavi H, Saghazadeh A, van den Heuvel L. et al. Peripheral blood levels of brain-derived neurotrophic factor in patients with post-traumatic stress disorder (PTSD): A systematic review and meta-analysis. PLoS One 2020; 15 (11): e0241928 doi:10.1371/journal.pone.0241928
    CrossrefPubMedGoogle Scholar
  • 71 Kozlovsky N, Matar MA, Kaplan Z. et al. Long-term down-regulation of BDNF mRNA in rat hippocampal CA1 subregion correlates with PTSD-like behavioural stress response. Int J Neuropsychopharmacol 2007; 10: 741-758
    CrossrefPubMedGoogle Scholar
  • 72 Frodl T, Schule C, Schmitt G. et al. Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression. Arch Gen Psychiatry 2007; 64: 410-416
    CrossrefPubMedGoogle Scholar
  • 73 Border R, Johnson EC, Evans LM. et al. No support for historical candidate gene or candidate gene-by-interaction hypotheses for major depression across multiple large samples. Am J Psychiatry 2019; 176: 376-387
    CrossrefPubMedGoogle Scholar
  • 74 Kunugi H, Hashimoto R, Yoshida M. et al. A missense polymorphism (S205L) of the low-affinity neurotrophin receptor p75NTR gene is associated with depressive disorder and attempted suicide. Am J Med Genet B Neuropsychiatr Genet 2004; 129B: 44-46
    CrossrefPubMedGoogle Scholar
  • 75 Gau YT, Liou YJ, Yu YW. et al. Evidence for association between genetic variants of p75 neurotrophin receptor (p75NTR) gene and antidepressant treatment response in Chinese major depressive disorder. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 594-599
    CrossrefPubMedGoogle Scholar