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


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.


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



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)


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© 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

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