Arsène Pinguelo, Ph.D. candidate
University of Toronto
Using cortical astrocytes and hippocampal neurons from fetal mice, investigators explore mechanisms that raise inhibitory tonic current (surface expression) linked to post-anesthetic cognitive deficits generated by the α5 subunit-containing GABAA Receptors (α5GABAARs) in mouse hippocampal neurons.
Key questions:
- What are the roles of anesthesia exposure, astrocytes, the pro-inflammatory cytokine IL-1β, and the protein kinase P38 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 GABAARs 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 α5GABAARs?
Findings show anesthetic activation of GABAARs 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 α5GABAAR surface expression and function. There is novel cross-talk between astrocytic and neuronal GABAARs—these may be targets that reduce post-anesthesia cognitive deficits.
Dr. Pinguelo:
“This research shows how a brief exposure to anesthesia can drive persistent changes in GABAA receptor function in neurons through cross-talk with astrocytes. This change in neuron GABAA function is linked to cognitive deficits and can lead to novel therapeutic targets”
“One of the most exciting results is that GABAA receptors in astrocytes can regulate GABAA 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.”