| First Author | Figueroa AG | Year | 2021 |
| Journal | J Neurophysiol | Volume | 126 |
| Issue | 4 | Pages | 1090-1100 |
| PubMed ID | 34406874 | Mgi Jnum | J:359184 |
| Mgi Id | MGI:7785368 | Doi | 10.1152/jn.00303.2021 |
| Citation | Figueroa AG, et al. (2021) Hippocampal beta2-GABA(A) receptors mediate LTP suppression by etomidate and contribute to long-lasting feedback but not feedforward inhibition of pyramidal neurons. J Neurophysiol 126(4):1090-1100 |
| abstractText | The general anesthetic etomidate, which acts through gamma-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) beta2-N265M mutation, we tested the roles of receptors that incorporate GABA(A) receptor beta2 versus beta3 subunits to suppression of long-term potentiation (LTP), a cellular model of learning and memory. We found that brain slices from beta2-N265M mice resisted etomidate suppression of LTP, indicating that the beta2-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, beta2 subunits are also expressed by pyramidal neurons, so they might also contribute. Therefore, using a previously established line of beta3-N265M mice, we also examined the contributions of beta2- versus beta3-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 beta2- and beta3-GABA(A)Rs contribute to GABA(A,slow) inhibition and that both beta2- and beta3-GABA(A)Rs contribute to feedback inhibition, whereas only beta3-GABA(A)Rs contribute to feedforward inhibition. We conclude that modulation of beta2-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 beta2-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. |
