title: CREB decreases astrocytic excitability by modifying subcellular calcium fluxes via the sigma-1 receptor.
abstract: Astrocytic excitability relies on cytosolic calcium increases as a key mechanism, whereby astrocytes contribute to synaptic transmission and hence learning and memory. While it is a cornerstone of neurosciences that experiences are remembered, because transmitters activate gene expression in neurons, long-term adaptive astrocyte plasticity has not been described. Here, we investigated whether the transcription factor CREB mediates adaptive plasticity-like phenomena in astrocytes. We found that activation of CREB-dependent transcription reduced the calcium responses induced by ATP, noradrenaline, or endothelin-1. As to the mechanism, expression of VP16-CREB, a constitutively active CREB mutant, had no effect on basal cytosolic calcium levels, extracellular calcium entry, or calcium mobilization from lysosomal-related acidic stores. Rather, VP16-CREB upregulated sigma-1 receptor expression thereby increasing the release of calcium from the endoplasmic reticulum and its uptake by mitochondria. Sigma-1 receptor was also upregulated in vivo upon VP16-CREB expression in astrocytes. We conclude that CREB decreases astrocyte responsiveness by increasing calcium signalling at the endoplasmic reticulum-mitochondria interface, which might be an astrocyte-based form of long-term depression.
authors.affiliation: Unitat de Bioquímica de Medicina, Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Edifici M, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Catalonia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Eraso-Pichot
authors.affiliation: Unitat de Bioquímica de Medicina, Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Edifici M, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Catalonia, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Larramona-Arcas
authors.affiliation: Unitat de Bioquímica de Medicina, Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Edifici M, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Catalonia, Spain.|Department of Neurosciences, School of Medicine, University of California, 9500 Gilman Dr, La Jolla, CA, 92093, USA.
authors.forename: E
authors.initials: E
authors.lastname: Vicario-Orri
authors.affiliation: Unitat de Bioquímica de Medicina, Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Edifici M, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Catalonia, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Villalonga
authors.affiliation: Unitat de Bioquímica de Medicina, Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Edifici M, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Catalonia, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Pardo
authors.affiliation: Unitat de Bioquímica de Medicina, Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Edifici M, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Catalonia, Spain. galea.inc@gmail.com.|Institució Catalana De Recerca I Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010, Barcelona, Catalonia, Spain. galea.inc@gmail.com.
authors.forename: E
authors.initials: E
authors.lastname: Galea
authors.affiliation: Unitat de Bioquímica de Medicina, Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Edifici M, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Catalonia, Spain. roser.masgrau@uab.cat.
authors.forename: R
authors.identifier: 0000-0002-6722-5939
authors.initials: R
authors.lastname: Masgrau
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation; D000097605:Sigma-1 Receptor
chemical_list: D002118:Calcium; D017362:Cyclic AMP Response Element-Binding Protein; D018377:Neurotransmitter Agents; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor
keywords: CEPIA indicators; Calcium signalling; Endoplasmic reticulum; MCU; Mitochondria; Mitochondria-associated membranes; VP16-CREB