title: General anesthesia selectively disrupts astrocyte calcium signaling in the awake mouse cortex.
abstract: Calcium signaling represents the principle pathway by which astrocytes respond to neuronal activity. General anesthetics are routinely used in clinical practice to induce a sleep-like state, allowing otherwise painful procedures to be performed. Anesthetic drugs are thought to mainly target neurons in the brain and act by suppressing synaptic activity. However, the direct effect of general anesthesia on astrocyte signaling in awake animals has not previously been addressed. This is a critical issue, because calcium signaling may represent an essential mechanism through which astrocytes can modulate synaptic activity. In our study, we performed calcium imaging in awake head-restrained mice and found that three commonly used anesthetic combinations (ketamine/xylazine, isoflurane, and urethane) markedly suppressed calcium transients in neocortical astrocytes. Additionally, all three anesthetics masked potentially important features of the astrocyte calcium signals, such as synchronized widespread transients that appeared to be associated with arousal in awake animals. Notably, anesthesia affected calcium transients in both processes and soma and depressed spontaneous signals, as well as calcium responses, evoked by whisker stimulation or agonist application. We show that these calcium transients are inositol 1,4,5-triphosphate type 2 receptor (IP(3)R2)-dependent but resistant to a local blockade of glutamatergic or purinergic signaling. Finally, we found that doses of anesthesia insufficient to affect neuronal responses to whisker stimulation selectively suppressed astrocyte calcium signals. Taken together, these data suggest that general anesthesia may suppress astrocyte calcium signals independently of neuronal activity. We propose that these glial effects may constitute a nonneuronal mechanism for sedative action of anesthetic drugs.
authors.affiliation: Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA. alexander.thrane@gmail.com
authors.forename: Alexander Stanley
authors.initials: AS
authors.lastname: Thrane
authors.forename: Vinita
authors.initials: V
authors.lastname: Rangroo Thrane
authors.forename: Douglas
authors.initials: D
authors.lastname: Zeppenfeld
authors.forename: Nanhong
authors.initials: N
authors.lastname: Lou
authors.forename: Qiwu
authors.initials: Q
authors.lastname: Xu
authors.forename: Erlend Arnulf
authors.initials: EA
authors.lastname: Nagelhus
authors.forename: Maiken
authors.initials: M
authors.lastname: Nedergaard
mesh_terms: D000768:Anesthesia, General; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D013569:Synapses / Q000378:metabolism*; D014851:Wakefulness / Q000187:drug effects*
chemical_list: D000777:Anesthetics; D053496:Inositol 1,4,5-Trisphosphate Receptors