Anesthetic Activation of GABA_A Receptors in Astrocytes Trigger a Persistent Increase in Cell-Surface Expression of α5GABA_A Receptors in Neurons via IL-1β in Mice

Arsène Pinguelo, PhD candidate, University of Toronto

Using cortical astrocytes and hippocampal neurons from fetal mice, investigators explored mechanisms that raise inhibitory tonic current (surface expression) linked to postanesthetic cognitive deficits generated by the α5 subunit-containing GABA_A receptors (α5GABA_ARs) in mouse hippocampal neurons in this poster session during the IARS 2021 Annual Meeting.

Key questions:

• What are the roles of anesthesia exposure, astrocytes, the proinflammatory cytokine IL-1β, and the protein kinase P38 mitogen-activated protein kinase (MAPK) signaling pathway in this process?
• What stimulates the release of IL-1β and does this promote phosphorylation of the P38 MAPK signaling pathway?
• Do anesthetic agents activate GABA_ARs in astrocytes and trigger the release of IL-1β that then acts on neurons through the P38 MAPK pathway to induce an increase in the cell surface expression of α5GABA_ARs?

Findings show anesthetic activation of GABA_ARs in astrocytes trigger the release of IL-1β from astrocytes. Released IL-1β acts on neurons through phosphorylation of P38 MAPK that drives an increase in α5GABA_AR surface expression and function. There is novel cross-talk between astrocytic and neuronal GABA_ARs. These may be targets that reduce postanesthesia cognitive deficits.

Dr. Pinguelo shared insights about his research.

What are/were the goals of the research in your poster session?

“This research shows how a brief exposure to anesthesia can drive persistent changes in GABA_A receptor function in neurons through cross-talk with astrocytes. This change in neuron GABA_A function is linked to cognitive deficits and can lead to novel therapeutic targets.” 

What is most significant about your research and/or the most significant result?

“One of the most exciting results is that GABA_A receptors in astrocytes can regulate GABA_A receptors in neurons. To date, most studies have focused on neurons. My research brings astrocytes, the most abundant cell type in the brain, to the forefront of investigations into perioperative neurocognitive disorders.”