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Furin promotes dendritic morphogenesis and learning and memory in transgenic mice

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Abstract

Furin is a proprotein convertase implicated in a variety of pathological processes including neurodegenerative diseases. However, the role of furin in neuronal plasticity and learning and memory remains to be elucidated. Here, we report that in brain-specific furin transgenic (Furin-Tg) mice, the dendritic spine density and proliferation of neural progenitor cells were significantly increased. These mice exhibited enhanced long-term potentiation (LTP) and spatial learning and memory performance, without alterations of miniature excitatory/inhibitory postsynaptic currents. In the cortex and hippocampus of Furin-Tg mice, the ratio of mature brain-derived neurotrophic factor (mBDNF) to pro-BDNF, and the activities of extracellular signal-related kinase (ERK) and cAMP response element-binding protein (CREB) were significantly elevated. We also found that hippocampal knockdown of CREB diminished the facilitation of LTP and cognitive function in Furin-Tg mice. Together, our results demonstrate that furin enhances dendritic morphogenesis and learning and memory in transgenic mice, which may be associated with BDNF–ERK–CREB signaling pathway.

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References

  1. Thomas G (2002) Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol 3:753–766

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Nakayama K (1997) Furin: a mammalian subtilisin/Kex2p-like endoprotease involved in processing of a wide variety of precursor proteins. Biochem J 327(Pt 3):625–635

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Scamuffa N, Calvo F, Chretien M, Seidah NG, Khatib AM (2006) Proprotein convertases: lessons from knockouts. FASEB J 20:1954–1963

    Article  PubMed  CAS  Google Scholar 

  4. Schroeder NE, Androwski RJ, Rashid A, Lee H, Lee J et al (2013) Dauer-specific dendrite arborization in C. elegans is regulated by KPC-1/Furin. Curr Biol 23:1527–1535

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Salzberg Y, Ramirez-Suarez NJ, Bulow HE (2014) The proprotein convertase KPC-1/furin controls branching and self-avoidance of sensory dendrites in Caenorhabditis elegans. PLoS Genet 10:e1004657

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Seidah NG, Benjannet S, Pareek S, Chretien M, Murphy RA (1996) Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases. FEBS Lett 379:247–250

    Article  PubMed  CAS  Google Scholar 

  7. Yang M, Lim Y, Li X, Zhong JH, Zhou XF (2011) Precursor of brain-derived neurotrophic factor (proBDNF) forms a complex with Huntingtin-associated protein-1 (HAP1) and sortilin that modulates proBDNF trafficking, degradation, and processing. J Biol Chem 286:16272–16284

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Chen Y, Zhang J, Deng M (2015) Furin mediates brain-derived neurotrophic factor upregulation in cultured rat astrocytes exposed to oxygen-glucose deprivation. J Neurosci Res 93:189–194

    Article  PubMed  CAS  Google Scholar 

  9. Cao J, Tang Y, Li Y, Gao K, Shi X et al (2017) Behavioral changes and hippocampus glucose metabolism in APP/PS1 transgenic mice via electro-acupuncture at governor vessel acupoints. Front Aging Neurosci 9:5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. 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  PubMed  CAS  Google Scholar 

  11. Mizui T, Ishikawa Y, Kumanogoh H, Kojima M (2016) Neurobiological actions by three distinct subtypes of brain-derived neurotrophic factor: multi-ligand model of growth factor signaling. Pharmacol Res 105:93–98

    Article  PubMed  CAS  Google Scholar 

  12. Zagrebelsky M, Korte M (2014) Form follows function: BDNF and its involvement in sculpting the function and structure of synapses. Neuropharmacology 76 Pt C:628–638

    Article  PubMed  CAS  Google Scholar 

  13. Lipsky RH, Marini AM (2007) Brain-derived neurotrophic factor in neuronal survival and behavior-related plasticity. Ann N Y Acad Sci 1122:130–143

    Article  PubMed  CAS  Google Scholar 

  14. Leal G, Bramham CR, Duarte CB (2017) BDNF and hippocampal synaptic plasticity. Vitam Horm 104:153–195

    Article  PubMed  CAS  Google Scholar 

  15. Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA et al (2006) Storage of spatial information by the maintenance mechanism of LTP. Science 313:1141–1144

    Article  PubMed  CAS  Google Scholar 

  16. Whitlock JR, Heynen AJ, Shuler MG, Bear MF (2006) Learning induces long-term potentiation in the hippocampus. Science 313:1093–1097

    Article  PubMed  CAS  Google Scholar 

  17. Borchelt DR, Davis J, Fischer M, Lee MK, Slunt HH et al (1996) A vector for expressing foreign genes in the brains and hearts of transgenic mice. Genet Anal 13:159–163

    Article  PubMed  CAS  Google Scholar 

  18. Fujimori K, Yano M, Miyake H, Kimura H (2014) Termination mechanism of CREB-dependent activation of COX-2 expression in early phase of adipogenesis. Mol Cell Endocrinol 384:12–22

    Article  PubMed  CAS  Google Scholar 

  19. Zhang Y, Chen G, Gao B, Li Y, Liang S et al (2016) NR4A1 knockdown suppresses seizure activity by regulating surface expression of NR2B. Sci Rep 6:37713

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Chen DY, Bambah-Mukku D, Pollonini G, Alberini CM (2012) Glucocorticoid receptors recruit the CaMKIIalpha–BDNF–CREB pathways to mediate memory consolidation. Nat Neurosci 15:1707–1714

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Bambah-Mukku D, Travaglia A, Chen DY, Pollonini G, Alberini CM (2014) A positive autoregulatory BDNF feedback loop via C/EBPbeta mediates hippocampal memory consolidation. J Neurosci 34:12547–12559

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Alonso M, Vianna MR, Izquierdo I, Medina JH (2002) Signaling mechanisms mediating BDNF modulation of memory formation in vivo in the hippocampus. Cell Mol Neurobiol 22:663–674

    Article  PubMed  CAS  Google Scholar 

  23. Hu XT, Zhu BL, Zhao LG, Wang JW, Liu L et al (2017) Histone deacetylase inhibitor apicidin increases expression of the alpha-secretase ADAM10 through transcription factor USF1-mediated mechanisms. FASEB J 31:1482–1493

    Article  PubMed  CAS  Google Scholar 

  24. Moghaddam M, Bures J (1997) Rotation of water in the Morris water maze interferes with path integration mechanisms of place navigation. Neurobiol Learn Mem 68:239–251

    Article  PubMed  CAS  Google Scholar 

  25. Tang B, Luo D, Yang J, Xu XY, Zhu BL et al (2015) Modulation of AMPA receptor mediated current by nicotinic acetylcholine receptor in layer I neurons of rat prefrontal cortex. Sci Rep 5:14099

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Mathis DM, Furman JL, Norris CM (2011) Preparation of acute hippocampal slices from rats and transgenic mice for the study of synaptic alterations during aging and amyloid pathology. J Vis Exp 23:2330

    Google Scholar 

  27. Kuipers SD, Trentani A, Tiron A, Mao X, Kuhl D et al (2016) BDNF-induced LTP is associated with rapid Arc/Arg3.1-dependent enhancement in adult hippocampal neurogenesis. Sci Rep 6:21222

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Tada T, Sheng M (2006) Molecular mechanisms of dendritic spine morphogenesis. Curr Opin Neurobiol 16:95–101

    Article  PubMed  CAS  Google Scholar 

  29. Lai KO, Ip NY (2013) Structural plasticity of dendritic spines: the underlying mechanisms and its dysregulation in brain disorders. Biochim Biophys Acta 1832:2257–2263

    Article  PubMed  CAS  Google Scholar 

  30. Wang B, Wang Z, Sun L, Yang L, Li H et al (2014) The amyloid precursor protein controls adult hippocampal neurogenesis through GABAergic interneurons. J Neurosci 34:13314–13325

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Kneussel M, Hausrat TJ (2016) Postsynaptic neurotransmitter receptor reserve pools for synaptic potentiation. Trends Neurosci 39:170–182

    Article  PubMed  CAS  Google Scholar 

  32. Deng-Bryant Y, Leung LY, Caudle K, Tortella F, Shear D (2016) Cognitive evaluation using morris water maze in neurotrauma. Methods Mol Biol 1462:539–551

    Article  PubMed  CAS  Google Scholar 

  33. Lynch MA (2004) Long-term potentiation and memory. Physiol Rev 84:87–136

    Article  PubMed  CAS  Google Scholar 

  34. Raymond CR (2007) LTP forms 1, 2 and 3: different mechanisms for the “long” in long-term potentiation. Trends Neurosci 30:167–175

    Article  PubMed  CAS  Google Scholar 

  35. Ehrlich DE, Josselyn SA (2016) Plasticity-related genes in brain development and amygdala-dependent learning. Genes Brain Behav 15:125–143

    Article  PubMed  CAS  Google Scholar 

  36. Ying SW, Futter M, Rosenblum K, Webber MJ, Hunt SP et al (2002) Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci 22:1532–1540

    Article  PubMed  CAS  Google Scholar 

  37. Posada-Duque RA, Ramirez O, Hartel S, Inestrosa NC, Bodaleo F et al (2017) CDK5 downregulation enhances synaptic plasticity. Cell Mol Life Sci 74:153–172

    Article  PubMed  CAS  Google Scholar 

  38. Gao H, Yan P, Zhang S, Huang H, Huang F et al (2016) Long-term dietary alpha-linolenic acid supplement alleviates cognitive impairment correlate with activating hippocampal CREB signaling in natural aging rats. Mol Neurobiol 53:4772–4786

    Article  PubMed  CAS  Google Scholar 

  39. Shonesy BC, Jalan-Sakrikar N, Cavener VS, Colbran RJ (2014) CaMKII: a molecular substrate for synaptic plasticity and memory. Prog Mol Biol Transl Sci 122:61–87

    Article  PubMed  CAS  Google Scholar 

  40. Murakoshi H, Shin ME, Parra-Bueno P, Szatmari EM, Shibata AC et al (2017) Kinetics of endogenous CaMKII required for synaptic plasticity revealed by optogenetic kinase inhibitor. Neuron 94(37–47):e35

    Google Scholar 

  41. Segal M (2017) Dendritic spines: morphological building blocks of memory. Neurobiol Learn Mem 138:3–9

    Article  PubMed  Google Scholar 

  42. Alonso M, Medina JH, Pozzo-Miller L (2004) ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons. Learn Mem 11:172–178

    Article  PubMed  PubMed Central  Google Scholar 

  43. Huber KM, Klann E, Costa-Mattioli M, Zukin RS (2015) Dysregulation of mammalian target of rapamycin signaling in mouse models of autism. J Neurosci 35:13836–13842

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Koshimizu H, Kiyosue K, Hara T, Hazama S, Suzuki S et al (2009) Multiple functions of precursor BDNF to CNS neurons: negative regulation of neurite growth, spine formation and cell survival. Mol Brain 2:27

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Zagrebelsky M, Holz A, Dechant G, Barde YA, Bonhoeffer T et al (2005) The p75 neurotrophin receptor negatively modulates dendrite complexity and spine density in hippocampal neurons. J Neurosci 25:9989–9999

    Article  PubMed  CAS  Google Scholar 

  46. Ebrahimi S, Okabe S (2014) Structural dynamics of dendritic spines: molecular composition, geometry and functional regulation. Biochim Biophys Acta 1838:2391–2398

    Article  PubMed  CAS  Google Scholar 

  47. Caviness VS Jr, Nowakowski RS, Bhide PG (2009) Neocortical neurogenesis: morphogenetic gradients and beyond. Trends Neurosci 32:443–450

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Tiyanont K, Wales TE, Aste-Amezaga M, Aster JC, Engen JR et al (2011) Evidence for increased exposure of the Notch1 metalloprotease cleavage site upon conversion to an activated conformation. Structure 19:546–554

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Zhang K, Zhao T, Huang X, Wu LY, Wu K et al (2014) Notch1 mediates postnatal neurogenesis in hippocampus enhanced by intermittent hypoxia. Neurobiol Dis 64:66–78

    Article  PubMed  CAS  Google Scholar 

  50. Jedlicka P, Vlachos A, Schwarzacher SW, Deller T (2008) A role for the spine apparatus in LTP and spatial learning. Behav Brain Res 192:12–19

    Article  PubMed  Google Scholar 

  51. Bekinschtein P, Cammarota M, Medina JH (2014) BDNF and memory processing. Neuropharmacology 76 Pt C:677–683

    Article  PubMed  CAS  Google Scholar 

  52. Bramham CR, Messaoudi E (2005) BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 76:99–125

    Article  PubMed  CAS  Google Scholar 

  53. Sherwood NT, Lo DC (1999) Long-term enhancement of central synaptic transmission by chronic brain-derived neurotrophic factor treatment. J Neurosci 19:7025–7036

    Article  PubMed  CAS  Google Scholar 

  54. Bolton MM, Lo DC, Sherwood NT (2000) Long-term regulation of excitatory and inhibitory synaptic transmission in hippocampal cultures by brain-derived neurotrophic factor. Prog Brain Res 128:203–218

    Article  PubMed  CAS  Google Scholar 

  55. Meis S, Endres T, Lessmann V (2012) Postsynaptic BDNF signalling regulates long-term potentiation at thalamo-amygdala afferents. J Physiol 590:193–208

    Article  PubMed  CAS  Google Scholar 

  56. Bramham CR (2008) Local protein synthesis, actin dynamics, and LTP consolidation. Curr Opin Neurobiol 18:524–531

    Article  PubMed  CAS  Google Scholar 

  57. Korte M, Kang H, Bonhoeffer T, Schuman E (1998) A role for BDNF in the late-phase of hippocampal long-term potentiation. Neuropharmacology 37:553–559

    Article  PubMed  CAS  Google Scholar 

  58. Minichiello L, Korte M, Wolfer D, Kühn R, Unsicker K et al (1999) Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24:401–414

    Article  PubMed  CAS  Google Scholar 

  59. Tyler WJ, Alonso M, Bramham CR, Pozzo-Miller LD (2002) From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem 9:224–237

    Article  PubMed  PubMed Central  Google Scholar 

  60. Lonze BE, Ginty DD (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron 35:605–623

    Article  PubMed  CAS  Google Scholar 

  61. Sakamoto K, Karelina K, Obrietan K (2011) CREB: a multifaceted regulator of neuronal plasticity and protection. J Neurochem 116:1–9

    Article  PubMed  CAS  Google Scholar 

  62. English JD, Sweatt JD (1997) A requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation. J Biol Chem 272:19103–19106

    Article  PubMed  CAS  Google Scholar 

  63. Gooney M, Shaw K, Kelly A, O’Mara SM, Lynch MA (2002) Long-term potentiation and spatial learning are associated with increased phosphorylation of TrkB and extracellular signal-regulated kinase (ERK) in the dentate gyrus: evidence for a role for brain-derived neurotrophic factor. Behav Neurosci 116:455–463

    Article  PubMed  CAS  Google Scholar 

  64. Davis S, Vanhoutte P, Pages C, Caboche J, Laroche S (2000) The MAPK/ERK cascade targets both Elk-1 and cAMP response element-binding protein to control long-term potentiation-dependent gene expression in the dentate gyrus in vivo. J Neurosci 20:4563–4572

    Article  PubMed  CAS  Google Scholar 

  65. Impey S, Obrietan K, Wong ST, Poser S, Yano S et al (1998) Cross talk between ERK and PKA is required for Ca2 + stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 21:869–883

    Article  PubMed  CAS  Google Scholar 

  66. Wetsel WC, Rodriguiz RM, Guillemot J, Rousselet E, Essalmani R et al (2013) Disruption of the expression of the proprotein convertase PC7 reduces BDNF production and affects learning and memory in mice. Proc Natl Acad Sci USA 110:17362–17367

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Barco A, Marie H (2011) Genetic approaches to investigate the role of CREB in neuronal plasticity and memory. Mol Neurobiol 44:330–349

    Article  PubMed  CAS  Google Scholar 

  68. Pittenger C, Huang YY, Paletzki RF, Bourtchouladze R, Scanlin H et al (2002) Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory. Neuron 34:447–462

    Article  PubMed  CAS  Google Scholar 

  69. Murphy DD, Segal M (1997) Morphological plasticity of dendritic spines in central neurons is mediated by activation of cAMP response element binding protein. Proc Natl Acad Sci USA 94:1482–1487

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Casadio A, Martin KC, Giustetto M, Zhu H, Chen M et al (1999) A transient, neuron-wide form of CREB-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis. Cell 99:221–237

    Article  PubMed  CAS  Google Scholar 

  71. Finkbeiner S, Tavazoie SF, Maloratsky A, Jacobs KM, Harris KM et al (1997) CREB: a major mediator of neuronal neurotrophin responses. Neuron 19:1031–1047

    Article  PubMed  CAS  Google Scholar 

  72. Yang Y, Zhou Q (2009) Spine modifications associated with long-term potentiation. Neuroscientist 15:464–476

    Article  PubMed  CAS  Google Scholar 

  73. Wang Z, Yan P, Hui T, Zhang J (2014) Epigenetic upregulation of PSD-95 contributes to the rewarding behavior by morphine conditioning. Eur J Pharmacol 732:123–129

    Article  PubMed  CAS  Google Scholar 

  74. Xu W (2011) PSD-95-like membrane associated guanylate kinases (PSD-MAGUKs) and synaptic plasticity. Curr Opin Neurobiol 21:306–312

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Zhao JP, Murata Y, Constantine-Paton M (2013) Eye opening and PSD95 are required for long-term potentiation in developing superior colliculus. Proc Natl Acad Sci USA 110:707–712

    Article  PubMed  Google Scholar 

  76. Leal G, Afonso PM, Salazar IL, Duarte CB (2015) Regulation of hippocampal synaptic plasticity by BDNF. Brain Res 1621:82–101

    Article  PubMed  CAS  Google Scholar 

  77. Butko MT, Yang J, Geng Y, Kim HJ, Jeon NL et al (2012) Fluorescent and photo-oxidizing TimeSTAMP tags track protein fates in light and electron microscopy. Nat Neurosci 15:1742–1751

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Ortega-Martinez S (2015) A new perspective on the role of the CREB family of transcription factors in memory consolidation via adult hippocampal neurogenesis. Front Mol Neurosci 8:46

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Keifer J, Zheng Z, Ambigapathy G (2015) A microRNA-BDNF negative feedback signaling loop in brain: implications for Alzheimer’s disease. Microrna 4:101–108

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81220108010 to G.-J. Chen; 31500821 to B.-L. Zhu; 81622015 and 81571042 to Z.-F. Dong).

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Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, 400016, China

    Binglin Zhu, Lige Zhao, Dong Luo, Demei Xu, Ying Tang, Zhuo Min, Xiaojuan Deng & Guojun Chen

  2. Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children’s Hospital of Chongqing Medical University, 136 Zhongshan Er Lu, Chongqing, 400014, China

    Tao Tan & Zhifang Dong

  3. Department of Physiology, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Fei Sun

  4. Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY, 14214, USA

    Zhen Yan

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  1. Binglin Zhu
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  2. Lige Zhao
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  3. Dong Luo
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  11. Zhen Yan
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  12. Guojun Chen
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Contributions

B-LZ and G-JC designed the experiments. B-LZ, L-GZ, YT, ZM and D-MX performed the experiments and the statistical analysis. B-L Zhu and G-J Chen wrote the manuscript. All authors contributed to preparation of the manuscript and approved the final contributions.

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Correspondence to Guojun Chen.

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Zhu, B., Zhao, L., Luo, D. et al. Furin promotes dendritic morphogenesis and learning and memory in transgenic mice. Cell. Mol. Life Sci. 75, 2473–2488 (2018). https://doi.org/10.1007/s00018-017-2742-3

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