A Perfect Storm: Consequences of Excess Inhibitory Neurotransmission after Anaesthesia and Surgery

Perioperative neurocognitive disorders may arise from three complementary mechanisms that, together, cause excessive inhibitory neurotransmission. Sustained accumulation of type A γ-aminobutyric acid (GABAA) receptors on the surface of neurones, aberrant release of GABA from astrocytes, and increased production of hydrogen peroxide (H2O2) can all enhance the amplitude of tonic inhibitory conductance, and in concert could disrupt network synchrony and impair cognition after anaesthesia and surgery. The report by Wan and colleagues identifies a key pathway by which sevoflurane activates calcium (Ca2+)/calmodulin-dependent protein kinase II (CaMKII), which impairs GABAA receptor internalisation and thereby promotes receptor accumulation on the neuronal surface. The accumulation of GABAA receptors is expected to interact synergistically with increased concentrations of GABA and H2O2 to drive excess inhibitory neurotransmission. Targeting even one of these three factors might be sufficient to preserve cognition after anaesthesia and surgery.