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Vitale, C.* ; Natali, G.* ; Cerullo, M.S.* ; Floss, T. ; Michetti, C.* ; Grasselli, G.* ; Benfenati, F.*

The homeostatic effects of the RE-1 silencing transcription factor on cortical networks are altered under ictogenic conditions in the mouse.

Acta Physiol. 240:e14146 (2024)

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AIM: The Repressor Element-1 Silencing Transcription Factor (REST) is an epigenetic master regulator playing a crucial role in the nervous system. In early developmental stages, REST downregulation promotes neuronal differentiation and the acquisition of the neuronal phenotype. In addition, postnatal fluctuations in REST expression contribute to shaping neuronal networks and maintaining network homeostasis. Here we investigate the role of the early postnatal deletion of neuronal REST in the assembly and strength of excitatory and inhibitory synaptic connections. METHODS: We investigated excitatory and inhibitory synaptic transmission by patch-clamp recordings in acute neocortical slices in a conditional knockout mouse model (Rest^GTi) in which Rest was deleted by delivering PHP.eB adeno-associated viruses encoding CRE recombinase under the control of the human synapsin I promoter in the lateral ventricles of P0-P1 pups. RESULTS: We show that, under physiological conditions, Rest deletion increased the intrinsic excitability of principal cortical neurons in the primary visual cortex and the density and strength of excitatory synaptic connections impinging on them, without affecting inhibitory transmission. Conversely, in the presence of a pathological excitation/inhibition imbalance induced by pentylenetetrazol, Rest deletion prevented the increase in synaptic excitation and decreased seizure severity. CONCLUSION: The data indicate that REST exerts distinct effects on the excitability of cortical circuits depending on whether it acts under physiological conditions or in the presence of pathologic network hyperexcitability. In the former case, REST preserves a correct excitatory/inhibitory balance in cortical circuits, while in the latter REST loses its homeostatic activity and may become pro-epileptogenic.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Rest Conditional Knockout ; Rest/nrsf ; Epilepsy ; Seizure Propensity ; Synaptic Transmission; Developmental Switch; Plasticity; Chromatin; Promotes; Disease; Rest; Nrsf

ISSN (print) / ISBN 1748-1708

e-ISSN 1748-1716

Journal Acta Physiologica

Quellenangaben Volume: 240, Issue: 6, Article Number: e14146

Publisher Wiley

Publishing Place Hoboken

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Developmental Genetics (IDG)

Grants Ministero della Salute
Ministero dell'Università e della Ricerca
Compagnia di San Paolo
IRCCS Ospedale Policlinico San Martino