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Papers of the Week

Papers: 2 Dec 2023 - 8 Dec 2023

2023 Nov 30

Transl Res


Editor's Pick

Crosstalk between GABA receptors in astrocytes and neurons triggered by general anesthetic drugs.


Wang DS, Ju L, Pinguelo AG, Kaneshwaran K, Haffey SC, Lecker I, Gohil H, Wheeler MB, Kaustov L, Ariza A, Yu M, Volchuk A, Steinberg BE, Goldenberg NM, Orser BA


General anesthetic drugs cause cognitive deficits that persist after the drugs have been eliminated. Astrocytes may contribute to such cognition-impairing effects through the release of one or more paracrine factors that increase a tonic inhibitory conductance generated by extrasynaptic γ-aminobutyric acid type A (GABA) receptors in hippocampal neurons. The mechanisms underlying this astrocyte-to-neuron crosstalk remain unknown. Interestingly, astrocytes express anesthetic-sensitive GABA receptors. Here, we tested the hypothesis that anesthetic drugs activate astrocytic GABA receptors to initiate crosstalk leading to a persistent increase in extrasynaptic GABA receptor function in neurons. We also investigated the signaling pathways in neurons and aimed to identify the paracrine factors released from astrocytes. Astrocytes and neurons from mice were grown in primary cell cultures and studied using in vitro electrophysiological and biochemical assays. We discovered that the commonly used anesthetics etomidate (injectable) and sevoflurane (inhaled) stimulated astrocytic GABA receptors to release paracrine factors, which increased the tonic current in neurons via a p38 MAPK-dependent signaling pathway. The increase in tonic current was mimicked by exogenous IL-1β and abolished by blocking IL-1 receptors; however, unexpectedly, IL-1β and other cytokines were not detected in astrocyte-conditioned media. In summary, we have identified a novel form of crosstalk between GABA receptors in astrocytes and neurons that engages a p38 MAPK-dependent pathway.