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Mol Neurobiol. 2018 Jun;55(6):4959-4972. doi: 10.1007/s12035-017-0698-9. Epub 2017 Aug 7.

REST-Dependent Presynaptic Homeostasis Induced by Chronic Neuronal Hyperactivity.

Author information

1
Department of Experimental Medicine, Section of Physiology, University of Genova, Viale Benedetto XV 3, 16132, Genoa, Italy.
2
Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132, Genoa, Italy.
3
Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132, Genoa, Italy. g.lignani@ucl.ac.uk.
4
Institute of Neurology, University College of London, WC1N 3BG, London, UK. g.lignani@ucl.ac.uk.
5
Pharmacology and Brain Pathology Lab, Humanitas Clinical and Research Center, Humanitas University, Via Manzoni 56, Rozzano, Milan, Italy.
6
Neurocure NWFZ, Charite Universitaetsmedizin Berlin, Chariteplatz 1, 10117, Berlin, Germany.
7
Laboratory of Neurosciences and Neurogenetics, Department of Head and Neck Diseases, "G. Gaslini" Institute, Via Gerolamo Gaslini 5, 16147, Genoa, Italy.
8
Department of Experimental Medicine, Section of Physiology, University of Genova, Viale Benedetto XV 3, 16132, Genoa, Italy. pietro.baldelli@unige.it.
9
Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132, Genoa, Italy. pietro.baldelli@unige.it.

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:

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

PMID:
28786015
DOI:
10.1007/s12035-017-0698-9
[Indexed for MEDLINE]

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