OBJECTIVE Many antiseizure drugs (ASDs) act on voltage-dependent sodium channels, and the molecular basis of these effects is well established. In contrast, how ASDs act on the level of neuronal networks is much less understood. METHODS In the present study, we determined the effects of eslicarbazepine (S-Lic) on different types of inhibitory neurons, as well as inhibitory motifs. Experiments were performed in hippocampal slices from both sham-control and chronically epileptic pilocarpine-treated rats. RESULTS We found that S-Lic causes an unexpected reduction of feed-forward inhibition in the CA1 region at high concentrations (300 µM), but not at lower concentrations (100 µM). Concurrently, 300 but not 100 μM S-Lic significantly reduced maximal firing rates in putative feed-forward interneurons located in the CA1 stratum radiatum of sham-control and epileptic animals. In contrast, feedback inhibition was not inhibited by S-Lic. Instead, application of S-Lic, in contrast to previous data for other drugs like carbamazepine (CBZ), resulted in a lasting potentiation of feedback inhibitory post-synaptic currents (IPSCs) only in epileptic and not in sham-control animals, which persisted after washout of S-Lic. We hypothesized that this plasticity of inhibition might rely on anti-Hebbian potentiation of excitatory feedback inputs onto oriens-lacunosum moleculare (OLM) interneurons, which is dependent on Ca2+ -permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Indeed, we show that blocking Ca2+ -permeable AMPA receptors completely prevents upmodulation of feedback inhibition. SIGNIFICANCE These results suggest that S-Lic affects inhibitory circuits in the CA1 hippocampal region in unexpected ways. In addition, ASD actions may not be sufficiently explained by acute effects on their target channels, rather, it may be necessary to take plasticity of inhibitory circuits into account.

中文翻译：

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艾司利卡西平对慢性实验性癫痫抑制微网络的复杂作用

目的 许多抗癫痫药 (ASD) 作用于电压依赖性钠通道，这些作用的分子基础已得到很好的确立。相比之下，ASD 如何在神经元网络水平上发挥作用则知之甚少。方法 在本研究中，我们确定了艾司利卡西平 (S-Lic) 对不同类型的抑制性神经元以及抑制性基序的影响。在来自假对照和慢性癫痫毛果芸香碱治疗的大鼠的海马切片中进行实验。结果 我们发现 S-Lic 在高浓度 (300 µM) 下导致 CA1 区域的前馈抑制意外降低，但在较低浓度 (100 µM) 下不会。同时，300 但不是 100 μM S-Lic 显着降低了位于假对照和癫痫动物 CA1 辐射层中的假定前馈中间神经元的最大放电率。相反，S-Lic 不抑制反馈抑制。相反，与卡马西平 (CBZ) 等其他药物的先前数据相比，S-Lic 的应用导致反馈抑制性突触后电流 (IPSC) 的持续增强仅在癫痫动物而非假对照动物中持续增强S-Lic 冲洗后。我们假设这种抑制的可塑性可能依赖于兴奋性反馈输入到 Oriens-lacunosum 分子 (OLM) 中间神经元的抗 Hebbian 增强，这依赖于 Ca2+ -可渗透的 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic酸 (AMPA) 受体。确实，我们表明阻断 Ca2+ 可渗透的 AMPA 受体完全阻止了反馈抑制的上调。意义 这些结果表明 S-Lic 以意想不到的方式影响 CA1 海马区的抑制回路。此外，ASD 行为可能无法通过对其目标通道的急性影响来充分解释，相反，可能有必要考虑抑制回路的可塑性。