Astrocytic GABAergic signaling in perioperative neurocognitive disorders: mechanisms and intervention strategies

Perioperative neurocognitive disorders (PND) are a major burden for older surgical patients, yet little is known about the cellular events that set them in motion, and no therapy currently changes their course. Anesthesia and amnesia after etomidate, sevoflurane, or isoflurane depend mainly on gamma-aminobutyric acid type A receptors (GABA(A)Rs), and an increasing body of work shows that astrocytes also respond to these drugs. This review examines an astrocyte-centered GABAergic cascade that may link anesthetic exposure to PND and grades the strength of the evidence at each node. When anesthetics engage astrocytic GABA(A)Rs, reactive astrogliosis follows, astrocytic GABA synthesis rises through the monoamine oxidase B (MAOB)-dependent putrescine route, and Best-1-mediated release along with weaker GABA transporter-3 (GAT-3) clearance lets ambient GABA accumulate. Extrasynaptic α5-GABA(A)Rs then become overactive, tonic inhibition of hippocampal and subcortical neurons may grow, synaptic plasticity falters, and cognition declines. We weigh the evidence behind each stage, distinguish mechanisms established in PND models from those extrapolated from other conditions, identify the astrocyte-specific experiments that remain to be performed, and consider interventions that could break the cascade, spanning α5-GABA(A)R negative modulation, MAOB blockade, GABA clearance repair, and dexmedetomidine. The astrocytic GABAergic axis therefore offers a promising candidate target for PND prevention and treatment, and we close by identifying priorities for translational research.