Astrocyte morphological remodeling regulates consciousness state transitions induced by inhaled general anesthesia

Abstract

General anesthetics (GAs) are conventionally thought to induce loss of consciousness (LOC) by acting on pre- and post-synaptic targets. However, the mechanism underlying the involvement of astrocytes in LOC remains unclear. Here we report that inhaled GAs cause reversible impairments in the fine processes of astrocytes within the somatosensory cortex, mediated by regulating the phosphorylation level of Ezrin, a protein critical for the fine morphology of astrocytes. Genetically deleting Ezrin or disrupting its phosphorylation was sufficient to decrease astrocyte-synapse interaction and enhance sensitivity to sevoflurane (Sevo) in vivo. Moreover, we show that disrupting astrocytic Ezrin phosphorylation boosted the inhibitory effect of Sevo on pyramidal neurons by enhancing tonic GABA and lowering excitability under anesthesia. Our work reveals previously unappreciated phosphorylation-dependent morphological dynamics, which enable astrocytes to regulate neuronal activity during the transition between two brain consciousness states.