Targeting γ-aminobutyric acid type A receptors to mitigate perioperative neurocognitive disorders: a narrative review

Perioperative neurocognitive disorders are common complications after anaesthesia and surgery, particularly among older adults. A growing body of preclinical evidence implicates dysregulation of extrasynaptic γ-aminobutyric acid type A (GABA_A) receptors as a key contributor to these disorders. Unlike synaptic GABA_A receptors that mediate synaptic or phasic inhibition, extrasynaptic GABA_A receptors, that often contain α5 and δ receptor subunits, generate a tonic inhibitory conductance that regulates neuronal excitability and network dynamics. Most anaesthetic drugs are well known to potentiate fast GABAergic inhibitory neurotransmission, but these agents also trigger persistent increases in the cell-surface expression of extrasynaptic GABA_A receptors, especially in brain regions that are critical for cognition such as the hippocampus and prefrontal cortex. Surgery and inflammation similarly cause excess cell-surface expression of extrasynaptic GABA_A receptors. The increased number of receptors enhances the amplitude of a tonic inhibitory current, which disrupts network plasticity and impairs learning, memory, and executive function. This narrative review explores the mechanistic links between perioperative care and alterations in the cell-surface expression of extrasynaptic GABA_A receptors, and the implications of such mechanisms in perioperative neurocognitive disorders. On the basis of these insights, we propose several potential prevention and treatment strategies.