Department of Anesthesiology, University of Wisconsin-Madison, Madison, Wisconsin.
Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
J Neurophysiol. 2021 Oct 1;126(4):1090-1100. doi: 10.1152/jn.00303.2021. Epub 2021 Aug 18.
The general anesthetic etomidate, which acts through γ-aminobutyric acid type A (GABA) 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 receptor (GABAR) β2-N265M mutation, we tested the roles of receptors that incorporate GABA 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-GABARs 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-GABARs to GABA 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-GABARs contribute to GABA inhibition and that both β2- and β3-GABARs contribute to feedback inhibition, whereas only β3-GABARs contribute to feedforward inhibition. We conclude that modulation of β2-GABARs is essential to etomidate suppression of LTP. Furthermore, to the extent that this occurs through GABARs on pyramidal neurons, it is through modulation of feedback inhibition. Etomidate exerts its anesthetic actions through GABA receptors. However, the mechanism remains unknown. Here, using a hippocampal brain slice model, we show that β2-GABARs 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.
全身麻醉药依托咪酯通过γ-氨基丁酸 A 型 (GABA) 受体发挥作用，在麻醉下会损害新记忆的形成。本研究旨在探讨其发生的分子和细胞机制。在这里，我们使用携带 GABA 受体 (GABAR) β2-N265M 突变的新型基因工程小鼠，测试了包含 GABA 受体 β2 与 β3 亚基的受体在抑制长时程增强 (LTP) 中的作用，LTP 是学习和记忆的细胞模型。我们发现，β2-N265M 小鼠的脑片抵抗依托咪酯对 LTP 的抑制，表明β2-GABAR 是该模型中的一个重要靶点。由于这些受体在海马体的中间神经元中表达最为丰富，这一发现支持中间神经元调节在依托咪酯控制突触可塑性中的作用。然而，β2 亚基也在锥体神经元中表达，因此它们也可能有贡献。因此，我们使用之前建立的β3-N265M 小鼠系，还研究了β2-与β3-GABAR 对 GABA 树突抑制的贡献，因为树突抑制特别适合控制突触可塑性。我们还研究了它们在通过前馈和反馈抑制控制群体活动的长时程抑制中的作用。我们发现，β2-和β3-GABAR 都有助于 GABA 抑制，β2-和β3-GABAR 都有助于反馈抑制，而只有β3-GABAR 有助于前馈抑制。我们的结论是，β2-GABAR 的调节对于依托咪酯抑制 LTP 是必不可少的。此外，在某种程度上，这种作用是通过锥体神经元上的 GABAR 来实现的，它是通过反馈抑制的调节来实现的。依托咪酯通过 GABA 受体发挥其麻醉作用。然而，其机制尚不清楚。在这里，我们使用海马脑片模型表明，β2-GABAR 对于这种效应是必不可少的。我们还表明，这些受体有助于锥体神经元的反馈抑制中持久的树突抑制，但不参与前馈抑制。这些发现对于理解麻醉剂如何阻断记忆形成，更广泛地说，对于理解抑制性电路如何控制学习和记忆具有重要意义。
