The general anesthetic etomidate, which acts through 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_AR β2-N265M mutation, we tested the roles of receptors that incorporate GABA_A receptor β2 vs. 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_ARs 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- vs. β3-GABA_ARs 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 both β2- and β3-GABA_ARs contribute to GABA_A,slow inhibition, and that both β2- and β3-GABA_ARs contribute to feedback inhibition, whereas only β3-GABA_ARs contribute to feedforward inhibition. We conclude that modulation of β2-GABA_ARs is essential to etomidate suppression of LTP. Furthermore, to the extent that this occurs through GABA_ARs on pyramidal neurons, it is through modulation of feedback inhibition.

中文翻译：

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海马 β2-GABAA 受体介导依托咪酯对 LTP 的抑制，并有助于长效反馈而非锥体神经元的前馈抑制

全身麻醉剂依托咪酯通过 GABA _A受体起作用，会损害麻醉下新记忆的形成。这项研究解决了发生这种情况的分子和细胞机制。_{在这里，我们使用携带 GABA A} R β2-N265M 突变的新基因工程小鼠系列，测试了包含 GABA _A受体 β2 与 β3 亚基的受体对抑制长时程增强 (LTP)的作用，LTP 是一种细胞模型的学习和记忆。我们发现来自 β2-N265M 小鼠的脑切片抵抗依托咪酯对 LTP 的抑制，表明 β2-GABA _ARs 是该模型中的基本目标。由于这些受体在海马体中由中间神经元表达最多，因此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。尽管如此，β2 亚基也由锥体神经元表达，因此它们也可能有所贡献。_{因此，使用先前建立的 β3-N265M 小鼠系，我们还检查了 β2- 与 β3-GABA A} Rs 对 GABA _A的贡献，即树突抑制缓慢，因为树突抑制特别适合控制突触可塑性。我们还通过前馈和反馈抑制检查了它们在长期抑制种群活动中的作用。我们发现 β2- 和 β3-GABA _A Rs 都有助于 GABA _A，缓慢抑制，并且 β2- 和 β3-GABA _ARS都有助于反馈抑制，而只有 β3-GABA _ARS有助于前馈抑制。我们得出结论，β2-GABA _A Rs 的调节对于依托咪酯抑制 LTP 至关重要。此外，在某种程度上，这是通过锥体神经元上的 GABA _A Rs 发生的，它是通过调节反馈抑制。