Skip to main content
SpringerLink
Log in

Distinct effects on the dendritic arbor occur by microbead versus bath administration of brain-derived neurotrophic factor

  • Original Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Proper communication among neurons depends on an appropriately formed dendritic arbor, and thus, aberrant changes to the arbor are implicated in many pathologies, ranging from cognitive disorders to neurodegenerative diseases. Due to the importance of dendritic shape to neuronal network function, the morphology of dendrites is tightly controlled and is influenced by both intrinsic and extrinsic factors. In this work, we examine how brain-derived neurotrophic factor (BDNF), one of the most well-studied extrinsic regulators of dendritic branching, affects the arbor when it is applied locally via microbeads to cultures of hippocampal neurons. We found that local application of BDNF increases both proximal and distal branching in a time-dependent manner and that local BDNF application attenuates pruning of dendrites that occurs with neuronal maturation. Additionally, we examined whether cytosolic PSD-95 interactor (cypin), an intrinsic regulator of dendritic branching, plays a role in these changes and found strong evidence for the involvement of cypin in BDNF-promoted increases in dendrites after 24 but not 48 h of application. This current study extends our previous work in which we found that bath application of BDNF for 72 h, but not shorter times, increases proximal dendrite branching and that this increase occurs through transcriptional regulation of cypin. Moreover, this current work illustrates how dendritic branching is regulated differently by the same growth factor depending on its spatial localization, suggesting a novel pathway for modulation of dendritic branching locally.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Koleske AJ (2013) Molecular mechanisms of dendrite stability. Nat Rev Neurosci 14:536–550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Segal RA (2003) Selectivity in neurotrophin signaling: theme and variations. Annu Rev Neurosci 26:299–330. doi:10.1146/annurev.neuro.26.041002.131421

    Article  CAS  PubMed  Google Scholar 

  3. McAllister AK, Katz LC, Lo DC (1996) Neurotrophin regulation of cortical dendritic growth requires activity. Neuron 17(6):1057–1064

    Article  CAS  PubMed  Google Scholar 

  4. Baker RE, Dijkhuizen PA, Van Pelt J, Verhaagen J (1998) Growth of pyramidal, but not non-pyramidal, dendrites in long-term organotypic explants of neonatal rat neocortex chronically exposed to neurotrophin-3. Eur J Neurosci 10(3):1037–1044

    Article  CAS  PubMed  Google Scholar 

  5. Jin X, Hu H, Mathers PH, Agmon A (2003) Brain-derived neurotrophic factor mediates activity-dependent dendritic growth in nonpyramidal neocortical interneurons in developing organotypic cultures. J Neurosci 23(13):5662–5673

    CAS  PubMed  Google Scholar 

  6. McAllister AK, Lo DC, Katz LC (1995) Neurotrophins regulate dendritic growth in developing visual cortex. Neuron 15:791–803

    Article  CAS  PubMed  Google Scholar 

  7. Dijkhuizen PA, Ghosh A (2005) BDNF regulates primary dendrite formation in cortical neurons via the PI3-kinase and MAP kinase signaling pathway. J Neurobiol 62(2):278–288. doi:10.1002/neu.20100

    Article  CAS  PubMed  Google Scholar 

  8. Horch HW, Kruttgen A, Portbury SD, Katz LC (1999) Destabilization of cortical dendrites and spines by BDNF. Neuron 23:353–364

    Article  CAS  PubMed  Google Scholar 

  9. Gao X, Smith GM, Chen J (2009) Impaired dendritic development and synaptic formation of postnatal-born dentate gyrus granular neurons in the absence of brain-derived neurotrophic factor signaling. Exp Neurol 215(1):178–190

    Article  CAS  PubMed  Google Scholar 

  10. Alder J, Kramer BC, Hoskin C, Thakker-Varia S (2012) Brain-derived neurotrophic Factor produced by human umbilical tissue-derived cells is required for its effect on hippocampal dendritic differentiation. Dev Neurobiol 72(6):755–765

    Article  CAS  PubMed  Google Scholar 

  11. Kuczewski N, Porche C, Lessmann V, Medina I, Gaiarsa J-L (2009) Activity-dependent dendritic release of BDNF and biological consequences. Mol Neurobiol 39:37–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Choi SH, Li Y, Parada LF, Sisodia SS (2009) Regulation of hippocampal progenitor cell survival, proliferation and dendritic development by BDNF. Mol Neurodegener. doi:10.1186/1750-1326-4-52

    Google Scholar 

  13. Park H, Poo M-M (2013) Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 14(1):7–23. doi:10.1038/nrn3379

    Article  CAS  PubMed  Google Scholar 

  14. Lazo OM, Gonzalez A, Ascaño M, Kuruvilla R, Couve A, Bronfman FC (2013) BDNF regulates Rab11-mediated recycling endosome dynamics to induce dendritic branching. J Neurosci 33(14):6112–6122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev 4(4):299–309

    Article  CAS  Google Scholar 

  16. Lu B, Nagappan G, Guan X, Nathan PJ, Wren P (2013) BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci 14:401–416

    Article  CAS  PubMed  Google Scholar 

  17. Barbacid M (1994) The Trk family of neurotrophin receptors. J Neurobiol 25(11):1386–1403

    Article  CAS  PubMed  Google Scholar 

  18. Nagappan G, Lu B (2005) Activity-dependent modulation of the BDNF receptor TrkB: mechanisms and implications. Trends Neurosci 28(9):464–471

    Article  CAS  PubMed  Google Scholar 

  19. Gupta VK, You Y, Gupta VB, Klistorner A, Graham SL (2013) TrkB receptor signalling: implications in neurodegenerative, psychiatric and proliferative disorders. Int J Mol Sci 14(5):10122–10142. doi:10.3390/ijms140510122

    Article  PubMed  PubMed Central  Google Scholar 

  20. Chapleau CA, Pozzo-Miller L (2012) Divergent roles of p75NTR and Trk receptors in BDNF’s effects on dendritic spine density and morphology. Neural Plast 2012:578057. doi:10.1155/2012/578057

    PubMed  PubMed Central  Google Scholar 

  21. Shooter EM (2001) Early days of the nerve growth factor proteins. Annu Rev Neurosci 24:601–629. doi:10.1146/annurev.neuro.24.1.601

    Article  CAS  PubMed  Google Scholar 

  22. Ghosh A, Carnahan J, Greenberg ME (1994) Requirement for BDNF in activity-dependent survival of cortical neurons. Science 263:1618–1623

    Article  CAS  PubMed  Google Scholar 

  23. Kwon M, Fernandez JR, Zegarek GF, Lo SB, Firestein BL (2011) BDNF-promoted increases in proximal dendrites occur via CREB-dependent transcriptional regulation of cypin. J Neurosci 31(26):9735–9745. doi:10.1523/JNEUROSCI.6785-10.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Horch HW, Katz LC (2002) BDNF release from single cells elicits local dendritic growth in nearby neurons. Nat Neurosci 5(11):1177–1184. doi:10.1038/nn927

    Article  CAS  PubMed  Google Scholar 

  25. Takei N, Inamura N, Kawamura M, Namba H, Hara K, Yonezawa K, Nawa H (2004) Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J Neurosci 24(44):9760–9769. doi:10.1523/JNEUROSCI.1427-04.2004

    Article  CAS  PubMed  Google Scholar 

  26. Yacoubian TA, Lo DC (2000) Truncated and full-length TrkB receptors regulate distinct modes of dendritic growth. Nat Neurosci 3(4):342–349. doi:10.1038/73911

    Article  CAS  PubMed  Google Scholar 

  27. Muragaki Y, Timothy N, Leight S, Hempstead BL, Chao MV, Trojanowski JQ, Lee VM (1995) Expression of trk receptors in the developing and adult human central and peripheral nervous system. J Comp Neurol 356(3):387–397. doi:10.1002/cne.903560306

    Article  CAS  PubMed  Google Scholar 

  28. Firestein BL, Firestein BL, Brenman JE, Aoki C, Sanchez-Perez AM, El-Husseini AE, Bredt DS (1999) Cypin: a cytosolic regulator of PSD-95 postsynaptic targeting. Neuron 24(3):659–672

    Article  CAS  PubMed  Google Scholar 

  29. Chen H, Firestein BL (2007) RhoA regulates dendrite branching in hippocampal neurons by decreasing cypin protein levels. J Neurosci 27(31):8378–8386

    Article  CAS  PubMed  Google Scholar 

  30. Jadali A, Kwan KY (2016) Activation of PI3 K signaling prevents aminoglycoside-induced hair cell death in the murine cochlea. Biol Open 5:698–708. doi:10.1242/bio.016758

    Article  PubMed  PubMed Central  Google Scholar 

  31. Norris A, Tammineni P, Wang S, Gerdes J, Murr A, Kwan KY, Cai Q, Grant BD (2017) SNX-1 and RME-8 oppose the assembly of HGRS-1/ESCRT-0 degradative microdomains on endosomes. Proc Natl Acad Sci 114(3):E307–E316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Henriques R, Lelek M, Fornasiero EF, Valtorta F, Zimmer C, Mhlanga MM (2010) QuickPALM: 3D real-time photoactivation nanoscopy image processing in ImageJ. Nat Methods 7(5):339–340. doi:10.1038/nmeth0510-339

    Article  CAS  PubMed  Google Scholar 

  33. Kutzing MK, Langhammer CG, Luo V, Lakdawala H, Firestein BL (2010) Automated Sholl analysis of digitized neuronal morphology at multiple scales. J Vis Exp. doi:10.3791/2354

    PubMed  PubMed Central  Google Scholar 

  34. Langhammer CG, Previtera ML, Sweet ES, Sran SS, Chen M, Firestein BL (2010) Automated Sholl analysis of digitized neuronal morphology at multiple scales: whole cell Sholl analysis versus Sholl analysis of arbor subregions. Cytometry Part A 77A(12):1160–1168. doi:10.1002/cyto.a.20954

    Article  Google Scholar 

  35. O’Neill KM, Akum BF, Dhawan ST, Kwon M, Langhammer CG, Firestein BL (2015) Assessing effects on dendritic arborization using novel Sholl analyses. Front Cell Neurosci 9:285

    PubMed  PubMed Central  Google Scholar 

  36. Yu X, Malenka RC (2004) Multiple functions for the cadherin/catenin complex during neuronal development. Neuropharmacology 47(5):779–786. doi:10.1016/j.neuropharm.2004.07.031

    Article  CAS  PubMed  Google Scholar 

  37. Charych EI, Akum BF, Goldberg JS, Jornsten RJ, Rongo C, Zheng JQ, Firestein BL (2006) Activity-independent regulation of dendrite patterning by postsynaptic density protein PSD-95. J Neurosci 26(40):10164–10176. doi:10.1523/JNEUROSCI.2379-06.2006

    Article  CAS  PubMed  Google Scholar 

  38. Akum BF, Chen M, Gunderson SI, Riefler GM, Scerri-Hansen MM, Firestein BL (2004) Cypin regulates dendrite patterning in hippocampal neurons by promoting microtubule assembly. Nat Neurosci 7(2):145–152. doi:10.1038/nn1179

    Article  CAS  PubMed  Google Scholar 

  39. Fernandez JR, Welsh WJ, Firestein BL (2008) Structural characterization of the zinc binding domain in cytosolic PSD-95 interactor (cypin): role of zinc binding in guanine deamination and dendrite branching. Proteins 70(3):873–881. doi:10.1002/prot.21683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. D’Este E, Baj G, Beuzer P, Ferrari E, Pinato G (2011) Use of optical tweezers technology for long-term, focal stimulation of specific subcellular neuronal compartments. Integr Biol 3:568–577

    Article  Google Scholar 

  41. Zhang XH, Poo MM (2002) Localized synaptic potentiation by BDNF requires local protein synthesis in the developing axon. Neuron 36(4):675–688

    Article  CAS  PubMed  Google Scholar 

  42. Armanini MP, McMahon SB, Sutherland J, Shelton DL, Phillips HS (1995) Truncated and catalytic isoforms of trkB are co-expressed in neurons of rat and mouse CNS. Eur J Neurosci 7(6):1403–1409

    Article  CAS  PubMed  Google Scholar 

  43. Biffo S, Offenhauser N, Carter BD, Barde YA (1995) Selective binding and internalisation by truncated receptors restrict the availability of BDNF during development. Development 121(8):2461–2470

    CAS  PubMed  Google Scholar 

  44. Frisen J, Verge VM, Fried K, Risling M, Persson H, Trotter J, Hokfelt T, Lindholm D (1993) Characterization of glial trkB receptors: differential response to injury in the central and peripheral nervous systems. Proc Natl Acad Sci USA 90(11):4971–4975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Rudge JS, Li Y, Pasnikowski EM, Mattsson K, Pan L, Yancopoulos GD, Wiegand SJ, Lindsay RM, Ip NY (1994) Neurotrophic factor receptors and their signal transduction capabilities in rat astrocytes. Eur J Neurosci 6(5):693–705

    Article  CAS  PubMed  Google Scholar 

  46. Wetmore C, Olson L (1995) Neuronal and nonneuronal expression of neurotrophins and their receptors in sensory and sympathetic ganglia suggest new intercellular trophic interactions. J Comp Neurol 353(1):143–159

    Article  CAS  PubMed  Google Scholar 

  47. Hartmann M, Brigadski T, Erdmann KS, Holtmann B, Sendtner M, Narz F, Leßmann V (2004) Truncated TrkB receptor-induced outgrowth of dendritic filopodia involves the p75 neurotrophin receptor. J Cell Sci 117:5803–5814

    Article  CAS  PubMed  Google Scholar 

  48. Baj G, Leone E, Chao MV, Tongiorgi E (2011) Spatial segregation of BDNF transcripts enables BDNF to differentially shape distinct dendritic compartments. Proc Natl Acad Sci 108(40):16813–16818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Fryer RH, Kaplan DR, Feinstein SC, Radeke MJ, Grayson DR, Kromer LF (1996) Developmental and mature expression of full-length and truncated TrkB receptors in the rat forebain. J Compar Neurol 374:21–40

    Article  CAS  Google Scholar 

  50. Ohira K, Shimizu K, Hayashi M (1999) Change of expression of full-length and truncated TrkBs in the developing monkey central nervous system. Dev Brain Res 112:21–29

    Article  CAS  Google Scholar 

  51. Ohira K, Hayashi M (2003) Expression of TrkB subtypes in the adult monkey cerebellar cortex. J Chem Neuroanat 25:175–183

    Article  CAS  PubMed  Google Scholar 

  52. Du J, Feng L, Zaitsev E, Je H-S, Liu X-w LuB (2003) Regulation of TrkB receptor tyrosine kinase and its internalization by neuronal activity and Ca2+ influx. J Cell Biol 163(2):385–395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Santi S, Cappello S, Riccio M, Bergami M, Aicardi G, Schenk U, Matteoli M, Canossa M (2006) Hippocampal neurons recycle BDNF for activity-dependent secretion and LTP maintenance. EMBO J 25:4372–4380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Vignoli B, Battistini G, Melani R, Blum R, Santi S, Berardi N, Canossa M (2016) Peri-synaptic glia recycles brain-derived neurotrophic factor for LTP stabilization and memory retention. Neuron 92:873–887

    Article  CAS  PubMed  Google Scholar 

  55. Sebastião AM, Assaife-Lopes N, Diógenes MJ, Vaz SH (1808) Ribeiro JA (2011) Modulation of brain-derived neurotrophic factor (BDNF) actions in the nervous system by adenosine A2A receptors and the role of lipid rafts. Biochem Biophys Acta 5:1340–1349

    Google Scholar 

  56. Zheng J, Shen W-H, Lu T-J, Zhou Y, Chen Q, Wang Z, Xiang T, Zhu Y-C, Zhang C, Duan S, Xiong Z-Q (2008) Clathrin-dependent endocytosis is required for TrkB-dependent Akt-mediated neuronal protection and dendritic growth. J Biol Chem 283(19):13280–13288

    Article  CAS  PubMed  Google Scholar 

  57. Dotti CG, Sullivan CA, Banker GA (1988) The establishment of polarity by hippocampal neurons in culture. J Neurosci 8(4):1454–1468

    CAS  PubMed  Google Scholar 

  58. Wu GY, Zou DJ, Rajan I, Cline H (1999) Dendritic dynamics in vivo change during neuronal maturation. J Neurosci 19(11):4472–4483

    CAS  PubMed  Google Scholar 

  59. Scott EK, Luo L (2001) How do dendrites take their shape? Nat Neurosci 4(4):359–365

    Article  CAS  PubMed  Google Scholar 

  60. Cline HT (2001) Dendritic arbor development and synaptogenesis. Curr Opin Neurobiol 11:118–126

    Article  CAS  PubMed  Google Scholar 

  61. Wong ROL, Ghosh A (2002) Activity-dependent regulation of dendritic growth and patterning. Nat Rev Neurosci 3:803–812

    Article  CAS  PubMed  Google Scholar 

  62. Deinhardt K, Chao MV (2014) Shaping neurons: long and short range effects of mature and proBDNF signalling upon neuronal structure. Neuropharmacology 76:603–609

    Article  CAS  PubMed  Google Scholar 

  63. Ji Y, Lu Y, Yang F, Shen W, Tang TT-T, Feng L, Duan S, Lu B (2010) Acute and gradual increases in BDNF concentration elicit distinct signaling and functions in neurons. Nat Neurosci 13(3):302–310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Singh KK, Park KJ, Hong EJ, Kramer BM, Greenberg ME, Kaplan DR, Miller FD (2008) Developmental axon pruning mediated by BDNF-p75nTR-dependent axon degeneration. Nat Neurosci 11(6):649–658

    Article  CAS  PubMed  Google Scholar 

  65. Horton AC, Yi JJ, Ehlers MD (2006) Cell type-specific dendritic polarity in the absence of spatially organized external cues. Brain Cell Biol 35(1):29–38

    Article  PubMed  Google Scholar 

  66. Baj G, Patrizio A, Montalbano A, Sciancalepore M, Tongiorgi E (2014) Developmental and maintenance defects in Rett syndrome neurons identified by a new mouse staging system in vitro. Front Cell Neurosci 8:18

    Article  PubMed  PubMed Central  Google Scholar 

  67. Edelmann E, Leßmann V, Brigadski T (2014) Pre- and postsynaptic twists in BDNF secretion and action in synaptic plasticity. Neuropharmacology 76:610–627

    Article  CAS  PubMed  Google Scholar 

  68. Kuczewski N, Porcher C, Ferrand N, Fiorentino H, Pellegrino C, Kolarow R, Lessmann V, Medina I, Gaiarsa J-L (2008) Backpropagating action potentials trigger dendritic release of BDNF during spontaneous network activity. J Neurosci 28(27):7013–7023

    Article  CAS  PubMed  Google Scholar 

  69. Stenovec M, Lasič E, Božić M, Bobnar Saša T, Stout Randy F, Grubišić V, Parpura V, Zorec R (2016) Ketamine inhibits ATP-evoked exocytotic release of Brain-Derived Neurotrophic Factor from vesicles in cultured rat astrocytes. Mol Neurobiol 53(10):6882–6896

    Article  CAS  PubMed  Google Scholar 

  70. Takemoto T, Ishihara Y, Ishida A, Yamazaki T (2015) Neuroprotection elicited by nerve growth factor and brain-derived neurotrophic factor released from astrocytes in response to methylmercury. Environ Toxicol Pharmacol 40:199–205

    Article  CAS  PubMed  Google Scholar 

  71. Mitre M, Mariga A, Chao MV (2017) Neurotrophin signalling: novel insights into mechanisms and pathophysiology. Clin Sci 131(1):13–23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hall D, Dhilla A, Charalambous A, Gogos JA, Karayiorgou M (2003) Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder. Am J Hum Genet 73:370–376. doi:10.1086/377003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112:257–269

    Article  CAS  PubMed  Google Scholar 

  74. Szeszko PR, Lipsky R, Mentschel C, Robinson D, Gunduz-Bruce H, Sevy S, Ashtari M, Napolitano B, Bilder RM, Kane JM, Goldman D, Malhotra AK (2005) Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation. Mol Psychiatry 10:631–636

    Article  CAS  PubMed  Google Scholar 

  75. Barbey AK, Colom R, Paul E, Forbes C, Krueger F, Goldman D, Grafman J (2014) Preservation of general intelligence following traumatic brain injury: contributions of the Met66 brain-derived neurotrophic factor. PLoS One 9(2):e88733

    Article  PubMed  PubMed Central  Google Scholar 

  76. Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ, Herrera DG, Toth M, Yang C, McEwen BS, Hempstead BL, Lee FS (2006) Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 314(5796):140–143. doi:10.1126/science.1129663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. An JJ, Gharami K, Liao GY, Woo NH, Lau AG, Vanevski F, Torre ER, Jones KR, Feng Y, Lu B, Xu B (2008) Distinct role of long 3′ UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell 134(1):175–187. doi:10.1016/j.cell.2008.05.045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Vicario A, Colliva A, Ratti A, Davidovic L, Baj G, Gricman Ł, Colombrita C, Pallavicini A, Jones K, Bardoni B, Tongiorgi E (2015) Dendritic targeting of short and long 3′ UTR BDNF mRNA is regulated by BDNF or NT-3 and distinct sets of RNA-binding proteins. Front Mol Neurosci 8:62

    Article  PubMed  PubMed Central  Google Scholar 

  79. Vanevski F, Xu B (2015) HuD interacts with Bdnf mRNA and is essential for activity-induced BDNF synthesis in dendrites. PLoS ONE 10(2):e0117264

    Article  PubMed  PubMed Central  Google Scholar 

  80. Aid T, Kazantseva A, Piirsoo M, Palm K (2007) Mouse and rat BDNF gene structure and expression revisited. J Neurosci Res 85:525–535

    Article  CAS  PubMed  Google Scholar 

  81. Mallei A, Baj G, Ieraci A, Corna S, Musazzi L, Lee FS, Tongiorgi E, Popoli M (2015) Expression and dendritic trafficking of BDNF-6 splice variant are impaired in knock-in mice carrying human BDNF Val66Met polymorphism. Int J Neuropsychopharmacol 18(12):1–10

    Article  CAS  Google Scholar 

  82. Baj G, Carlino D, Gardossi L, Tongiorgi E (2013) Toward a unified biological hypothesis for the BDNF Val66Met-associated memory deficits in humans: a model of impaired dendritic mRNA trafficking. Front Neurosci 7:188. doi:10.3389/fnins.2013.00188

    Article  PubMed  PubMed Central  Google Scholar 

  83. Baj G, Pinhero V, Vaghi V, Tongiorgi E (2016) Signaling pathways controlling activity-dependent local translation of BDNF and their localization in dendritic arbors. J Cell Sci 129:2852–2864

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work is funded in part by National Science Foundation grants IOS-0919747 and IOS-1353724 (to BLF). KMO is supported by the National Institutes of Health under the Ruth L. Kirschstein National Research Service Award 5 T32 GM008339 from the NIGMS, a Predoctoral Fellowship from the New Jersey Commission on Brain Injury Research #CBIR13FEL002, and a Predoctoral GAANN Fellowship #P200A150131 from the DOE. KED was awarded Aresty Research Funding from Rutgers University. The authors would also like to thank Dr. Kelvin Kwan (Rutgers University) for his generous help with imaging of the microbeads.

Author information

Author notes

  1. Kate M. O’Neill and Munjin Kwon contributed equally.

Authors and Affiliations

  1. Department of Cell Biology & Neuroscience, Rutgers University, 604 Allison Road, Piscataway, NJ, 08854, USA

    Kate M. O’Neill, Munjin Kwon, Katherine E. Donohue & Bonnie L. Firestein

  2. Graduate Program in Biomedical Engineering Rutgers University, Piscataway, NJ, USA

    Kate M. O’Neill

  3. Biomedical Engineering Graduate Faculty Rutgers University, Piscataway, NJ, USA

    Bonnie L. Firestein

Authors
  1. Kate M. O’Neill
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Munjin Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katherine E. Donohue
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bonnie L. Firestein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bonnie L. Firestein.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

18_2017_2589_MOESM1_ESM.tif

Supplementary Figure 1: Bead distribution along the dendritic arbor. Bead distance from the cell body was measured if beads were within 4.5 μm of a dendrite. Bead distributions are plotted in 20 μm increments. Part 1. Bead distribution along the dendritic arbor is highly correlated between the conditions at different time points. Pearson’s r coefficient is 0.9371, 0.9787, 0.9629, and 0.9773 for 5h, 24h, 48h, and 72h, respectively. Part 2. Bead distribution is highly correlated between treatment conditions in neurons transfected with identical shRNA plasmids. For neurons transfected with GST shRNA, Pearson’s r is 0.9321, 0.8980, and 0.9769 for 5h, 24h, and 48h, respectively. For neurons transfected with cypin shRNA, Pearson’s r is 0.9726, 0.9676, and 0.8708 for 5h, 24h, and 48h, respectively (TIFF 959 kb)

18_2017_2589_MOESM2_ESM.tif

Supplementary Figure 2: Average number of dendrites per neuron is significantly increased after treatment with BDNF-coated beads for at least 48 hours. A. Treatment with BDNF-coated beads for 5 hours does not significantly change the average number of dendrites per neuron. B. Treatment with BDNF-coated beads for 24 hours does not significantly change the average number of dendrites per neuron. C. Treatment with BDNF-coated beads for 48 hours significantly increases the average number of dendrites per neuron (*p<0.05). D. Treatment with BDNF-coated beads for 72 hours significantly increases the average number of dendrites per neuron (*p<0.05). Statistics calculated by Student’s t-test. Error bars indicate SEM (TIFF 793 kb)

18_2017_2589_MOESM3_ESM.tif

Supplementary Figure 3: Order-specific analysis of dendrite numbers reveals that treatment with BDNF-coated beads significantly affects distinct orders of dendrites in a time-dependent manner. A-C. Analysis of dendrites of neurons treated for 5 hours with BSA- or BDNF-coated beads. A. Treatment with BDNF-coated beads does not significantly change the number of primary dendrites. B. Treatment with BDNF-coated beads significantly decreases the number of secondary dendrites (*p<0.05). C. Treatment with BDNF-coated beads does not significantly change the number of tertiary and higher order dendrites. D-F. Analysis of dendrites of neurons treated for 24 hours with BSA- or BDNF-coated beads. D. Treatment with BDNF-coated beads significantly increases the number of primary dendrites (**p<0.01). E. Treatment with BDNF-coated beads does not significantly change the number of secondary dendrites. F. Treatment with BDNF-coated beads does not significantly change the number of tertiary and higher order dendrites. G-I. Analysis of dendrites of neurons treated for 48 hours with BSA- or BDNF-coated beads. G. Treatment with BDNF-coated beads does not significantly change the number of primary dendrites. H. Treatment with BDNF-coated beads does not significantly change the number of secondary dendrites. I. Treatment with BDNF-coated beads significantly increases the number of tertiary and higher order dendrites (*p<0.05). J-L. Analysis of dendrites of neurons treated for 72 hours with BSA- or BDNF-coated beads. J. Treatment with BDNF-coated beads significantly increases the number of primary dendrites (*p<0.05). K. Treatment with BDNF-coated beads significantly increases the number of secondary dendrites (*p<0.05). L. Treatment with BDNF-coated beads does not significantly change the number of tertiary and higher order dendrites. Statistics calculated by Student’s t-test. Error bars indicate SEM (TIFF 1260 kb)

18_2017_2589_MOESM4_ESM.tif

Supplementary Figure 4: Average dendrite length per neuron is not altered by treatment with BDNF-coated beads. A. Treatment with BDNF-coated beads for 5 hours does not significantly change the average length of dendrites per neuron. B. Treatment with BDNF-coated beads for 24 hours does not significantly change the average length of dendrites per neuron. C. Treatment with BDNF-coated beads for 48 hours does not significantly change the average length of dendrites per neuron. D. Treatment with BDNF-coated beads for 72 hours does not significantly change the average length of dendrites per neuron. Statistics calculated by Student’s t-test. Error bars indicate SEM. (TIFF 917 kb)

18_2017_2589_MOESM5_ESM.tif

Supplementary Figure 5: Order-specific analysis of dendrite lengths reveals that treatment with BDNF-coated beads significantly increases the length of tertiary and higher order dendrites after 72 hours. A-C. Analysis of dendrites of neurons treated for 5 hours with BSA- or BDNF-coated beads. A. Treatment with BDNF-coated beads does not significantly change the average length of primary dendrites. B. Treatment with BDNF-coated beads does not significantly change the average length of secondary dendrites. C. Treatment with BDNF-coated beads does not significantly change the average length of tertiary and higher order dendrites. D-F. Analysis of dendrites of neurons treated for 24 hours with BSA- or BDNF-coated beads. D. Treatment with BDNF-coated beads does not significantly change the average length of primary dendrites. E. Treatment with BDNF-coated beads does not significantly change the average length of secondary dendrites. F. Treatment with BDNF-coated beads does not significantly change the average length of tertiary and higher order dendrites. G-I. Analysis of dendrites of neurons treated for 48 hours with BSA- or BDNF-coated beads. G. Treatment with BDNF-coated beads does not significantly change the average length of primary dendrites. H. Treatment with BDNF-coated beads does not significantly change the average length of secondary dendrites. I. Treatment with BDNF-coated beads does not significantly change the average length of tertiary and higher order dendrites. J-L. Analysis of dendrites of neurons treated for 72 hours with BSA- or BDNF-coated beads. J. Treatment with BDNF-coated beads does not significantly change the average length of primary dendrites. K. Treatment with BDNF-coated beads does not significantly change the average length of secondary dendrites. L. Treatment with BDNF-coated beads significantly increases the average length of tertiary and higher order dendrites (*p<0.05). Statistics calculated by Student’s t-test. Error bars indicate SEM (TIFF 1404 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

O’Neill, K.M., Kwon, M., Donohue, K.E. et al. Distinct effects on the dendritic arbor occur by microbead versus bath administration of brain-derived neurotrophic factor. Cell. Mol. Life Sci. 74, 4369–4385 (2017). https://doi.org/10.1007/s00018-017-2589-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-017-2589-7

Keywords

Search

Navigation