title: REST/NRSF-mediated intrinsic homeostasis protects neuronal networks from hyperexcitability.
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.
authors.affiliation: 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.
authors.forename: Davide
authors.initials: D
authors.lastname: Pozzi
authors.forename: Gabriele
authors.initials: G
authors.lastname: Lignani
authors.forename: Enrico
authors.initials: E
authors.lastname: Ferrea
authors.forename: Andrea
authors.initials: A
authors.lastname: Contestabile
authors.forename: Francesco
authors.initials: F
authors.lastname: Paonessa
authors.forename: Rosalba
authors.initials: R
authors.lastname: D'Alessandro
authors.forename: Pellegrino
authors.initials: P
authors.lastname: Lippiello
authors.forename: Davide
authors.initials: D
authors.lastname: Boido
authors.forename: Anna
authors.initials: A
authors.lastname: Fassio
authors.forename: Jacopo
authors.initials: J
authors.lastname: Meldolesi
authors.forename: Flavia
authors.initials: F
authors.lastname: Valtorta
authors.forename: Fabio
authors.initials: F
authors.lastname: Benfenati
authors.forename: Pietro
authors.initials: P
authors.lastname: Baldelli
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009415:Nerve Net; D009474:Neurons / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D015761:4-Aminopyridine; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor