title: α1-Adrenergic receptors mediate coordinated Ca2+ signaling of cortical astrocytes in awake, behaving mice.
abstract: Astrocyte Ca2+ signals in awake behaving mice are widespread, coordinated and differ fundamentally from the locally restricted Ca2+ transients observed ex vivo and in anesthetized animals. Here we show that the synchronized release of norepinephrine (NE) from locus coeruleus (LC) projections throughout the cerebral cortex mediate long-ranging Ca2+ signals by activation of astrocytic α1-adrenergic receptors. When LC output was triggered by either physiological sensory (whisker) stimulation or an air-puff startle response, astrocytes responded with fast Ca2+ transients that encompassed the entire imaged field (positioned over either frontal or parietal cortex). The application of adrenergic inhibitors, including α1-adrenergic antagonist prazosin, potently suppressed both evoked, as well as the frequently observed spontaneous astroglial Ca2+ signals. The LC-specific neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), which reduced cortical NE content by >90%, prevented nearly all astrocytic Ca2+ signals in awake mice. The observations indicate that in adult, unanesthetized mice, astrocytes do not respond directly to glutamatergic signaling evoked by sensory stimulation. Instead astrocytes appear to be the primary target for NE, with astrocytic Ca2+ signaling being triggered by the α1-adrenergic receptor. In turn, astrocytes may coordinate the broad effects of neuromodulators on neuronal activity.
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642.
authors.forename: Fengfei
authors.initials: F
authors.lastname: Ding
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642.
authors.forename: John
authors.initials: J
authors.lastname: O'Donnell
authors.affiliation: Department of Ophthalmology, Haukeland University Hospital, Bergen 5021, Norway.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Thrane
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642.
authors.forename: Douglas
authors.initials: D
authors.lastname: Zeppenfeld
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642.
authors.forename: Hongyi
authors.initials: H
authors.lastname: Kang
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642.
authors.forename: Lulu
authors.initials: L
authors.lastname: Xie
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642.
authors.forename: Fushun
authors.initials: F
authors.lastname: Wang
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642.
authors.forename: Maiken
authors.initials: M
authors.lastname: Nedergaard
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D001596:Benzylamines / Q000494:pharmacology; D020013:Calcium Signaling; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D011224:Prazosin / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D001596:Benzylamines; D014179:Neurotransmitter Uptake Inhibitors; D018340:Receptors, Adrenergic, alpha-1; C012102:DSP 4; D009638:Norepinephrine; D011224:Prazosin
keywords: Astrocyte; Awake; Calcium; Norepinephrine; Startle