Centonze, E.* ; Marte, A.* ; Albini, M.* ; Rocchi, A.* ; Cesca, F.* ; Chiacchiaretta, M.* ; Floss, T. ; Baldelli, P.* ; Ferroni, S.* ; Benfenati, F.* ; Valente, P.*
Neuron-restrictive silencer factor/repressor element 1-silencing transcription factor (NRSF/REST) controls spatial K+ buffering in primary cortical astrocytes.
J. Neurochem. 165, 701-721 (2023)
Neuron-restrictive silencer factor/repressor element 1 (RE1)-silencing transcription factor (NRSF/REST) is a transcriptional repressor of a large cluster of neural genes containing RE1 motifs in their promoter region. NRSF/REST is ubiquitously expressed in non-neuronal cells, including astrocytes, while it is downregulated during neuronal differentiation. While neuronal NRSF/REST homeostatically regulates intrinsic excitability and synaptic transmission, the role of the high NRSF/REST expression levels in the homeostatic functions of astrocytes is poorly understood. Here, we investigated the functional consequences of NRSF/REST deletion in primary cortical astrocytes derived from NRSF/REST conditional knockout mice (KO). We found that NRSF/REST KO astrocyte displayed a markedly reduced activity of inward rectifying K+ channels subtype 4.1 (Kir4.1) underlying spatial K+ buffering that was associated with a decreased expression and activity of the glutamate transporter-1 (GLT-1) responsible for glutamate uptake by astrocytes. The effects of the impaired astrocyte homeostatic functions on neuronal activity were investigated by co-culturing wild type hippocampal neurons with NRSF/REST KO astrocytes. Interestingly, neurons experienced increased neuronal excitability at high firing rates associated with decrease afterhyperpolarization and increased amplitude of excitatory postsynaptic currents. The data indicate that astrocytic NRSF/REST directly participates in neural circuit homeostasis by regulating intrinsic excitability and excitatory transmission and that dysfunctions of NRSF/REST expression in astrocytes may contribute to the pathogenesis of neurological disorders.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Typ der Hochschulschrift
Herausgeber
Schlagwörter
Nrsf/rest ; Glutamate Uptake ; Potassium Channels ; Primary Astrocytes ; Synaptic Homeostasis ; Transcriptional Regulation; Rectifier Potassium Channel; Glutamate Transporters; Gene-expression; Ion Channels; Down-regulation; Knock-out; In-vivo; Kir4.1; Rest; Repressor
Keywords plus
Sprache
englisch
Veröffentlichungsjahr
2023
Prepublished im Jahr
0
HGF-Berichtsjahr
2023
ISSN (print) / ISBN
0022-3042
e-ISSN
1471-4159
ISBN
Bandtitel
Konferenztitel
Konferzenzdatum
Konferenzort
Konferenzband
Quellenangaben
Band: 165,
Heft: 5,
Seiten: 701-721
Artikelnummer: ,
Supplement: ,
Reihe
Verlag
Wiley
Verlagsort
111 River St, Hoboken 07030-5774, Nj Usa
Tag d. mündl. Prüfung
0000-00-00
Betreuer
Gutachter
Prüfer
Topic
Hochschule
Hochschulort
Fakultät
Veröffentlichungsdatum
0000-00-00
Anmeldedatum
0000-00-00
Anmelder/Inhaber
weitere Inhaber
Anmeldeland
Priorität
Begutachtungsstatus
Peer reviewed
POF Topic(s)
30204 - Cell Programming and Repair
Forschungsfeld(er)
Genetics and Epidemiology
PSP-Element(e)
G-500500-001
Förderungen
Italian Ministry of University and Research
Ricerca Corrente
IRCCS Ospedale Policlinico San Martino
Compagnia di San Paolo
Copyright
Erfassungsdatum
2023-01-17