Advertisement

Molecular Neurobiology

, Volume 55, Issue 6, pp 4959–4972 | Cite as

REST-Dependent Presynaptic Homeostasis Induced by Chronic Neuronal Hyperactivity

  • F. Pecoraro-Bisogni
  • Gabriele Lignani
  • A. Contestabile
  • E. Castroflorio
  • D. Pozzi
  • A. Rocchi
  • C. Prestigio
  • M. Orlando
  • P. Valente
  • M. Massacesi
  • F. Benfenati
  • Pietro Baldelli
Article

Abstract

Homeostatic plasticity is a regulatory feedback response in which either synaptic strength or intrinsic excitability can be adjusted up or down to offset sustained changes in neuronal activity. Although a growing number of evidences constantly provide new insights into these two apparently distinct homeostatic processes, a unified molecular model remains unknown. We recently demonstrated that REST is a transcriptional repressor critical for the downscaling of intrinsic excitability in cultured hippocampal neurons subjected to prolonged elevation of electrical activity. Here, we report that, in the same experimental system, REST also participates in synaptic homeostasis by reducing the strength of excitatory synapses by specifically acting at the presynaptic level. Indeed, chronic hyperactivity triggers a REST-dependent decrease of the size of synaptic vesicle pools through the transcriptional and translational repression of specific presynaptic REST target genes. Together with our previous report, the data identify REST as a fundamental molecular player for neuronal homeostasis able to downscale simultaneously both intrinsic excitability and presynaptic efficiency in response to elevated neuronal activity. This experimental evidence adds new insights to the complex activity-dependent transcriptional regulation of the homeostatic plasticity processes mediated by REST.

Keywords

Homeostatic plasticity REST Gene transcription Excitatory synapse Neuronal excitability Presynaptic terminals Synaptic vesicles 

Notes

Acknowledgements

This study was supported by research grants from the Italian Ministry of Health Bando Giovani Ricercatori (GR-2009-1473821 to P.B.), EUFP7 Integrating Project “Desire” (Grant no.602531), and EU ITN “ECMED” (Grant no. 642881) to F.B. The support of Telethon-Italy (Grant GGP13033; to F.B.) and CARIPLO Foundation (Grant nos. 2013-0879 and 2013-0735 to F.B.) are also acknowledged. We wish to thank Prof. Jacopo Meldolesi for helpful discussions and Dr. Silvia Casagrande for precious help with cell cultures.

Compliance with Ethical Standards

All experiments were performed in accordance with the guidelines established by the European Communities Council (Directive 2010/63/EU of September 22, 2010) and were approved by the Italian Ministry of Health.

Conflict of Interest

The authors declare that they have no competing interests.

Supplementary material

12035_2017_698_MOESM1_ESM.pdf (1.4 mb)
Suppl. Fig. 1 (PDF 1413 kb)
12035_2017_698_MOESM2_ESM.pdf (195 kb)
Suppl. Fig. 2 (PDF 194 kb)

References

  1. 1.
    Davis GW (2013) Homeostatic signaling and the stabilization of neural function. Neuron 80(3):718–728. doi: 10.1016/j.neuron.2013.09.044 CrossRefPubMedGoogle Scholar
  2. 2.
    Nelson SB, Turrigiano GG (2008) Strength through diversity. Neuron 60(3):477–482. doi: 10.1016/j.neuron.2008.10.020 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Davis GW (2006) Homeostatic control of neural activity: from phenomenology to molecular design. Annu Rev Neurosci 29:307–323. doi: 10.1146/annurev.neuro.28.061604.135751 CrossRefPubMedGoogle Scholar
  4. 4.
    Davis GW, Muller M (2015) Homeostatic control of presynaptic neurotransmitter release. Annu Rev Physiol 77:251–270. doi: 10.1146/annurev-physiol-021014-071740 CrossRefPubMedGoogle Scholar
  5. 5.
    Schanzenbacher CT, Sambandan S, Langer JD, Schuman EM (2016) Nascent proteome remodeling following homeostatic scaling at hippocampal synapses. Neuron 92(2):358–371. doi: 10.1016/j.neuron.2016.09.058 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Meadows JP, Guzman-Karlsson MC, Phillips S, Holleman C, Posey JL, Day JJ, Hablitz JJ, Sweatt JD (2015) DNA methylation regulates neuronal glutamatergic synaptic scaling. Sci Signal 8 (382):ra61. doi: 10.1126/scisignal.aab0715
  7. 7.
    Chong JA, Tapia-Ramirez J, Kim S, Toledo-Aral JJ, Zheng Y, Boutros MC, Altshuller YM, Frohman MA et al (1995) REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell 80(6):949–957Google Scholar
  8. 8.
    Schoenherr CJ, Anderson DJ (1995) The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science 267(5202):1360–1363CrossRefPubMedGoogle Scholar
  9. 9.
    Mandel G, Fiondella CG, Covey MV, Lu DD, Loturco JJ, Ballas N (2011) Repressor element 1 silencing transcription factor (REST) controls radial migration and temporal neuronal specification during neocortical development. Proc Natl Acad Sci U S A 108(40):16789–16794. doi: 10.1073/pnas.1113486108 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Sun YM, Greenway DJ, Johnson R, Street M, Belyaev ND, Deuchars J, Bee T, Wilde S et al (2005) Distinct profiles of REST interactions with its target genes at different stages of neuronal development. Mol Biol Cell 16(12):5630–5638. doi: 10.1091/mbc.E05-07-0687
  11. 11.
    Greenway DJ, Street M, Jeffries A, Buckley NJ (2007) RE1 silencing transcription factor maintains a repressive chromatin environment in embryonic hippocampal neural stem cells. Stem Cells 25(2):354–363. doi: 10.1634/stemcells.2006-0207 CrossRefPubMedGoogle Scholar
  12. 12.
    Johnson R, Teh CH, Kunarso G, Wong KY, Srinivasan G, Cooper ML, Volta M, Chan SS et al (2008) REST regulates distinct transcriptional networks in embryonic and neural stem cells. PLoS Biol 6(10):e256. doi: 10.1371/journal.pbio.0060256
  13. 13.
    Conaco C, Otto S, Han JJ, Mandel G (2006) Reciprocal actions of REST and a microRNA promote neuronal identity. Proc Natl Acad Sci U S A 103(7):2422–2427. doi: 10.1073/pnas.0511041103 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Otto SJ, McCorkle SR, Hover J, Conaco C, Han JJ, Impey S, Yochum GS, Dunn JJ et al (2007) A new binding motif for the transcriptional repressor REST uncovers large gene networks devoted to neuronal functions. J Neurosci 27(25):6729–6739. doi: 10.1523/JNEUROSCI.0091-07.2007
  15. 15.
    Tapia-Ramirez J, Eggen BJ, Peral-Rubio MJ, Toledo-Aral JJ, Mandel G (1997) A single zinc finger motif in the silencing factor REST represses the neural-specific type II sodium channel promoter. Proc Natl Acad Sci U S A 94(4):1177–1182CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Su X, Gopalakrishnan V, Stearns D, Aldape K, Lang FF, Fuller G, Snyder E, Eberhart CG et al (2006) Abnormal expression of REST/NRSF and Myc in neural stem/progenitor cells causes cerebellar tumors by blocking neuronal differentiation. Mol Cell Biol 26(5):1666–1678. doi: 10.1128/MCB.26.5.1666-1678.2006
  17. 17.
    Paquette AJ, Perez SE, Anderson DJ (2000) Constitutive expression of the neuron-restrictive silencer factor (NRSF)/REST in differentiating neurons disrupts neuronal gene expression and causes axon pathfinding errors in vivo. Proc Natl Acad Sci U S A 97(22):12318–12323. doi: 10.1073/pnas.97.22.12318 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Aoki H, Hara A, Era T, Kunisada T, Yamada Y (2012) Genetic ablation of rest leads to in vitro-specific derepression of neuronal genes during neurogenesis. Development 139(4):667–677. doi: 10.1242/dev.072272 CrossRefPubMedGoogle Scholar
  19. 19.
    Nechiporuk T, McGann J, Mullendorff K, Hsieh J, Wurst W, Floss T, Mandel G (2016) The REST remodeling complex protects genomic integrity during embryonic neurogenesis. elife 5:e09584. doi: 10.7554/eLife.09584 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Cargnin F, Nechiporuk T, Mullendorff K, Stumpo DJ, Blackshear PJ, Ballas N, Mandel G (2014) An RNA binding protein promotes axonal integrity in peripheral neurons by destabilizing REST. J Neurosci 34(50):16650–16661. doi: 10.1523/JNEUROSCI.1650-14.2014 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Calderone A, Jover T, Noh KM, Tanaka H, Yokota H, Lin Y, Grooms SY, Regis R et al (2003) Ischemic insults derepress the gene silencer REST in neurons destined to die. J Neurosci 23(6):2112–2121Google Scholar
  22. 22.
    Formisano L, Noh KM, Miyawaki T, Mashiko T, Bennett MV, Zukin RS (2007) Ischemic insults promote epigenetic reprogramming of mu opioid receptor expression in hippocampal neurons. Proc Natl Acad Sci U S A 104(10):4170–4175. doi: 10.1073/pnas.0611704104 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Noh KM, Hwang JY, Follenzi A, Athanasiadou R, Miyawaki T, Greally JM, Bennett MV, Zukin RS (2012) Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death. Proc Natl Acad Sci U S A 109(16):E962–E971. doi: 10.1073/pnas.1121568109 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kaneko N, Hwang JY, Gertner M, Pontarelli F, Zukin RS (2014) Casein kinase 1 suppresses activation of REST in insulted hippocampal neurons and halts ischemia-induced neuronal death. J Neurosci 34(17):6030–6039. doi: 10.1523/JNEUROSCI.4045-13.2014 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Palm K, Belluardo N, Metsis M, Timmusk T (1998) Neuronal expression of zinc finger transcription factor REST/NRSF/XBR gene. J Neurosci 18(4):1280–1296CrossRefPubMedGoogle Scholar
  26. 26.
    Spencer EM, Chandler KE, Haddley K, Howard MR, Hughes D, Belyaev ND, Coulson JM, Stewart JP et al (2006) Regulation and role of REST and REST4 variants in modulation of gene expression in in vivo and in vitro in epilepsy models. Neurobiol Dis 24(1):41–52. doi: 10.1016/j.nbd.2006.04.020
  27. 27.
    McClelland S, Flynn C, Dube C, Richichi C, Zha Q, Ghestem A, Esclapez M, Bernard C et al (2011) Neuron-restrictive silencer factor-mediated hyperpolarization-activated cyclic nucleotide gated channelopathy in experimental temporal lobe epilepsy. Ann Neurol 70(3):454–464. doi: 10.1002/ana.22479
  28. 28.
    Pozzi D, Lignani G, Ferrea E, Contestabile A, Paonessa F, D'Alessandro R, Lippiello P, Boido D et al (2013) REST/NRSF-mediated intrinsic homeostasis protects neuronal networks from hyperexcitability. EMBO J 32(22):2994–3007. doi: 10.1038/emboj.2013.231
  29. 29.
    Baldelli P, Meldolesi J (2015) The transcription repressor REST in adult neurons: physiology, pathology, and diseases(1,2,3). eNeuro 2(4). doi: 10.1523/ENEURO.0010-15.2015
  30. 30.
    Schoenherr CJ, Paquette AJ, Anderson DJ (1996) Identification of potential target genes for the neuron-restrictive silencer factor. Proc Natl Acad Sci U S A 93(18):9881–9886CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    McClelland S, Brennan GP, Dube C, Rajpara S, Iyer S, Richichi C, Bernard C, Baram TZ (2014) The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes. elife 3:e01267. doi: 10.7554/eLife.01267 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Baldelli P, Fassio A, Valtorta F, Benfenati F (2007) Lack of synapsin I reduces the readily releasable pool of synaptic vesicles at central inhibitory synapses. J Neurosci 27(49):13520–13531. doi: 10.1523/JNEUROSCI.3151-07.2007 CrossRefPubMedGoogle Scholar
  33. 33.
    Avoli M, D'Antuono M, Louvel J, Kohling R, Biagini G, Pumain R, D'Arcangelo G, Tancredi V (2002) Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro. Prog Neurobiol 68(3):167–207CrossRefPubMedGoogle Scholar
  34. 34.
    Ryan D, Drysdale AJ, Lafourcade C, Pertwee RG, Platt B (2009) Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J Neurosci 29(7):2053–2063. doi: 10.1523/JNEUROSCI.4212-08.2009 CrossRefPubMedGoogle Scholar
  35. 35.
    Ivenshitz M, Segal M (2010) Neuronal density determines network connectivity and spontaneous activity in cultured hippocampus. J Neurophysiol 104(2):1052–1060. doi: 10.1152/jn.00914.2009 CrossRefPubMedGoogle Scholar
  36. 36.
    Deidda G, Parrini M, Naskar S, Bozarth IF, Contestabile A, Cancedda L (2015) Reversing excitatory GABAAR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome. Nat Med 21(4):318–326. doi: 10.1038/nm.3827 CrossRefPubMedGoogle Scholar
  37. 37.
    Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3 (7):RESEARCH0034Google Scholar
  38. 38.
    Lignani G, Raimondi A, Ferrea E, Rocchi A, Paonessa F, Cesca F, Orlando M, Tkatch T et al (2013) Epileptogenic Q555X SYN1 mutant triggers imbalances in release dynamics and short-term plasticity. Hum Mol Genet 22(11):2186–2199. doi: 10.1093/hmg/ddt071
  39. 39.
    Verstegen AM, Tagliatti E, Lignani G, Marte A, Stolero T, Atias M, Corradi A, Valtorta F et al (2014) Phosphorylation of synapsin I by cyclin-dependent kinase-5 sets the ratio between the resting and recycling pools of synaptic vesicles at hippocampal synapses. J Neurosci 34(21):7266–7280. doi: 10.1523/JNEUROSCI.3973-13.2014
  40. 40.
    Fassio A, Patry L, Congia S, Onofri F, Piton A, Gauthier J, Pozzi D, Messa M et al (2011) SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function. Hum Mol Genet 20(12):2297–2307. doi: 10.1093/hmg/ddr122
  41. 41.
    Stevens CF (1993) Quantal release of neurotransmitter and long-term potentiation. Cell 72(Suppl):55–63CrossRefPubMedGoogle Scholar
  42. 42.
    De Gois S, Schafer MK, Defamie N, Chen C, Ricci A, Weihe E, Varoqui H, Erickson JD (2005) Homeostatic scaling of vesicular glutamate and GABA transporter expression in rat neocortical circuits. J Neurosci 25(31):7121–7133. doi: 10.1523/JNEUROSCI.5221-04.2005 CrossRefPubMedGoogle Scholar
  43. 43.
    Herman MA, Ackermann F, Trimbuch T, Rosenmund C (2014) Vesicular glutamate transporter expression level affects synaptic vesicle release probability at hippocampal synapses in culture. J Neurosci 34(35):11781–11791. doi: 10.1523/JNEUROSCI.1444-14.2014 CrossRefPubMedGoogle Scholar
  44. 44.
    Muller M, Liu KS, Sigrist SJ, Davis GW (2012) RIM controls homeostatic plasticity through modulation of the readily-releasable vesicle pool. J Neurosci 32(47):16574–16585. doi: 10.1523/JNEUROSCI.0981-12.2012 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Cesca F, Baldelli P, Valtorta F, Benfenati F (2010) The synapsins: key actors of synapse function and plasticity. Prog Neurobiol 91(4):313–348. doi: 10.1016/j.pneurobio.2010.04.006 CrossRefPubMedGoogle Scholar
  46. 46.
    Wu LG, Hamid E, Shin W, Chiang HC (2014) Exocytosis and endocytosis: modes, functions, and coupling mechanisms. Annu Rev Physiol 76:301–331. doi: 10.1146/annurev-physiol-021113-170305 CrossRefPubMedGoogle Scholar
  47. 47.
    Zhao C, Dreosti E, Lagnado L (2011) Homeostatic synaptic plasticity through changes in presynaptic calcium influx. J Neurosci 31(20):7492–7496. doi: 10.1523/JNEUROSCI.6636-10.2011 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Lin Y, Bloodgood BL, Hauser JL, Lapan AD, Koon AC, Kim TK, Hu LS, Malik AN et al (2008) Activity-dependent regulation of inhibitory synapse development by Npas4. Nature 455(7217):1198–1204. doi: 10.1038/nature07319
  49. 49.
    Ooi L, Wood IC (2007) Chromatin crosstalk in development and disease: lessons from REST. Nat Rev Genet 8(7):544–554. doi: 10.1038/nrg2100 CrossRefPubMedGoogle Scholar
  50. 50.
    Roopra A, Dingledine R, Hsieh J (2012) Epigenetics and epilepsy. Epilepsia 53(Suppl 9):2–10. doi: 10.1111/epi.12030 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Hwang JY, Kaneko N, Noh KM, Pontarelli F, Zukin RS (2014) The gene silencing transcription factor REST represses miR-132 expression in hippocampal neurons destined to die. J Mol Biol 426(20):3454–3466. doi: 10.1016/j.jmb.2014.07.032 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Zhao Y, Zhu M, Yu Y, Qiu L, Zhang Y, He L, Zhang J (2016) Brain REST/NRSF is not only a silent repressor but also an active protector. Mol Neurobiol. doi: 10.1007/s12035-015-9658-4
  53. 53.
    Rodenas-Ruano A, Chavez AE, Cossio MJ, Castillo PE, Zukin RS (2012) REST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors. Nat Neurosci 15(10):1382–1390. doi: 10.1038/nn.3214 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Garriga-Canut M, Schoenike B, Qazi R, Bergendahl K, Daley TJ, Pfender RM, Morrison JF, Ockuly J et al (2006) 2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP-dependent metabolic regulation of chromatin structure. Nat Neurosci 9(11):1382–1387. doi: 10.1038/nn1791
  55. 55.
    Hu XL, Cheng X, Cai L, Tan GH, Xu L, Feng XY, Lu TJ, Xiong H et al (2011) Conditional deletion of NRSF in forebrain neurons accelerates epileptogenesis in the kindling model. Cereb Cortex 21(9):2158–2165. doi: 10.1093/cercor/bhq284
  56. 56.
    Lu T, Aron L, Zullo J, Pan Y, Kim H, Chen Y, Yang TH, Kim HM et al (2014) REST and stress resistance in ageing and Alzheimer’s disease. Nature 507(7493):448–454. doi: 10.1038/nature13163
  57. 57.
    Nho K, Kim S, Risacher SL, Shen L, Corneveaux JJ, Swaminathan S, Lin H, Ramanan VK et al (2015) Protective variant for hippocampal atrophy identified by whole exome sequencing. Ann Neurol 77(3):547–552. doi: 10.1002/ana.24349
  58. 58.
    Yankner BA (2015) REST and Alzheimer disease. Ann Neurol 78(3):499. doi: 10.1002/ana.24420 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of Experimental Medicine, Section of PhysiologyUniversity of GenovaGenoaItaly
  2. 2.Center for Synaptic Neuroscience and TechnologyIstituto Italiano di TecnologiaGenoaItaly
  3. 3.Institute of NeurologyUniversity College of LondonLondonUK
  4. 4.Pharmacology and Brain Pathology Lab, Humanitas Clinical and Research CenterHumanitas UniversityMilanItaly
  5. 5.Neurocure NWFZCharite Universitaetsmedizin BerlinBerlinGermany
  6. 6.Laboratory of Neurosciences and Neurogenetics, Department of Head and Neck Diseases“G. Gaslini” InstituteGenoaItaly

Personalised recommendations