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

Davide Pozzi, Gabriele Lignani, Enrico Ferrea, Andrea Contestabile, Francesco Paonessa, Rosalba D'Alessandro, Pellegrino Lippiello, Davide Boido, Anna Fassio, Jacopo Meldolesi, Flavia Valtorta, Fabio Benfenati, Pietro Baldelli

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2994-3007
Number of pages14
JournalEMBO Journal
Volume32
Issue number22
DOIs
Publication statusPublished - Nov 13 2013

Keywords

  • 4-aminopyridine
  • excitability
  • intrinsic homeostasis
  • Na channels
  • transcriptional repression

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

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