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EMBO J. 2013 Nov 13;32(22):2994-3007. doi: 10.1038/emboj.2013.231. Epub 2013 Oct 22.

REST/NRSF-mediated intrinsic homeostasis protects neuronal networks from hyperexcitability.

Author information

1
1] Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy [2] Department of Neuroscience, San Raffaele Scientific Institute, Vita Salute University, Milano, Italy.

Abstract

Intrinsic homeostasis enables neuronal circuits to maintain activity levels within an appropriate range by modulating neuronal voltage-gated conductances, but the signalling pathways involved in this process are largely unknown. We characterized the process of intrinsic homeostasis induced by sustained electrical activity in cultured hippocampal neurons based on the activation of the Repressor Element-1 Silencing Transcription Factor/Neuron-Restrictive Silencer Factor (REST/NRSF). We showed that 4-aminopyridine-induced hyperactivity enhances the expression of REST/NRSF, which in turn, reduces the expression of voltage-gated Na(+) channels, thereby decreasing the neuronal Na(+) current density. This mechanism plays an important role in the downregulation of the firing activity at the single-cell level, re-establishing a physiological spiking activity in the entire neuronal network. Conversely, interfering with REST/NRSF expression impaired this homeostatic response. Our results identify REST/NRSF as a critical factor linking neuronal activity to the activation of intrinsic homeostasis and restoring a physiological level of activity in the entire neuronal network.

PMID:
24149584
PMCID:
PMC3831314
DOI:
10.1038/emboj.2013.231
[Indexed for MEDLINE]
Free PMC Article
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