Hippocampal β2-GABAA receptors mediate LTP suppression by etomidate and contribute to long-lasting feedback but not feedforward inhibition of pyramidal neurons

The general anesthetic etomidate, which acts through γ-aminobutyric acid type A (GABA A ) receptors, impairs the formation of new memories under anesthesia. This study addresses the molecular and cellular mechanisms by which this occurs. Here, using a new line of genetically engineered mice carrying the GABA A receptor (GABA A R) β2-N265M mutation, we tested the roles of receptors that incorporate GABA A receptor β2 versus β3 subunits to suppression of long-term potentiation (LTP), a cellular model of learning and memory. We found that brain slices from β2-N265M mice resisted etomidate suppression of LTP, indicating that the β2-GABA A Rs are an essential target in this model. As these receptors are most heavily expressed by interneurons in the hippocampus, this finding supports a role for interneuron modulation in etomidate control of synaptic plasticity. Nevertheless, β2 subunits are also expressed by pyramidal neurons, so they might also contribute. Therefore, using a previously established line of β3-N265M mice, we also examined the contributions of β2- versus β3-GABA A Rs to GABA A,slow dendritic inhibition, because dendritic inhibition is particularly well suited to controlling synaptic plasticity. We also examined their roles in long-lasting suppression of population activity through feedforward and feedback inhibition. We found that both β2- and β3-GABA A Rs contribute to GABA A,slow inhibition and that both β2- and β3-GABA A Rs contribute to feedback inhibition, whereas only β3-GABA A Rs contribute to feedforward inhibition. We conclude that modulation of β2-GABA A Rs is essential to etomidate suppression of LTP. Furthermore, to the extent that this occurs through GABA A Rs on pyramidal neurons, it is through modulation of feedback inhibition. NEW & NOTEWORTHY Etomidate exerts its anesthetic actions through GABA A receptors. However, the mechanism remains unknown. Here, using a hippocampal brain slice model, we show that β2-GABA A Rs are essential to this effect. We also show that these receptors contribute to long-lasting dendritic inhibition in feedback but not feedforward inhibition of pyramidal neurons. These findings hold implications for understanding how anesthetics block memory formation and, more generally, how inhibitory circuits control learning and memory.