Focal cortical dysplasia type IIb (FCDIIb) and tuberous sclerosis complex (TSC) are typical causes of developmental delay and refractory epilepsy. G‐protein‐coupled receptor 30 (GPR30) is a specific estrogen receptor that is critical in neurodevelopment, neuroinflammation, and neuronal excitability, suggesting that it plays a potential role in the epilepsy of patients with FCDIIb and TSC. Therefore, we investigated the role of GPR30 in patients with FCDIIb and TSC. We found that the expression of GPR30 and its downstream protein kinase A (PKA) pathway were decreased and negatively correlated with seizure frequency in female patients with FCDIIb and TSC, but not in male patients. GPR30 was widely distributed in neurons, astrocytes, and microglia, and its downregulation was especially notable in microglia. The GPR30 agonist G‐1 increased the expression of PKA and p‐PKA in cultured cortical neurons, and the GPR30 antagonist G‐15 exhibited the opposite effects of G‐1. The NF‐κB signaling pathway was also activated in the specimens of female patients with FCDIIb and TSC, and was regulated by G‐1 and G‐15 in cultured cortical neurons. We also found that GPR30 regulated cortical neuronal excitability by altering the frequency of spontaneous excitatory postsynaptic currents and the expression of NR2A/B. Further, the relationship between GPR30 and glycometabolism was evaluated by analyzing the correlations between GPR30 and ¹⁸F‐FDG PET‐CT values (standardized uptake values, SUVs). Positive correlations between GPR30 and SUVs were found in female patients, but not in male patients. Intriguingly, GPR30 expression and SUVs were significantly decreased in the epileptogenic tubers of female TSC patients, and ROC curves indicated that SUVs could predict the localization of epileptogenic tubers. Taken together, our results suggest a potential protective effect of GPR30 in the epileptogenesis of female patients with FCDIIb and TSC.

中文翻译：

---

局灶性皮质发育不良IIb型和结节性硬化症女性患者癫痫病灶中GPR30表达下调与18F-FDG PET-CT值相关

局灶性皮质发育不良 IIb 型 (FCDIIb) 和结节性硬化症 (TSC) 是发育迟缓和难治性癫痫的典型原因。G 蛋白偶联受体 30 (GPR30) 是一种特异性雌激素受体，对神经发育、神经炎症和神经元兴奋性至关重要，表明它在 FCDIIb 和 TSC 患者的癫痫中发挥潜在作用。因此，我们研究了 GPR30 在 FCDIIb 和 TSC 患者中的作用。我们发现 FCDIIb 和 TSC 女性患者 GPR30 及其下游蛋白激酶 A (PKA) 通路的表达降低并与癫痫发作频率呈负相关，而男性患者则不然。GPR30广泛分布于神经元、星形胶质细胞和小胶质细胞中，其下调在小胶质细胞中尤为显着。GPR30 激动剂 G-1 增加培养的皮层神经元中 PKA 和 p-PKA 的表达，GPR30 拮抗剂 G-15 表现出与 G-1 相反的作用。NF-κB 信号通路在 FCDIIb 和 TSC 女性患者的标本中也被激活，并在培养的皮层神经元中受 G-1 和 G-15 的调控。我们还发现 GPR30 通过改变自发兴奋性突触后电流的频率和 NR2A/B 的表达来调节皮质神经元的兴奋性。此外，通过分析 GPR30 与糖代谢之间的相关性，评估了 GPR30 与糖代谢之间的关系。并且在培养的皮层神经元中受 G-1 和 G-15 的调节。我们还发现 GPR30 通过改变自发兴奋性突触后电流的频率和 NR2A/B 的表达来调节皮质神经元的兴奋性。此外，通过分析 GPR30 与糖代谢之间的相关性，评估了 GPR30 与糖代谢之间的关系。并且在培养的皮层神经元中受 G-1 和 G-15 的调节。我们还发现 GPR30 通过改变自发兴奋性突触后电流的频率和 NR2A/B 的表达来调节皮质神经元的兴奋性。此外，通过分析 GPR30 与糖代谢之间的相关性，评估了 GPR30 与糖代谢之间的关系。¹⁸ F-FDG PET-CT 值（标准化摄取值，SUV）。在女性患者中发现 GPR30 和 SUV 之间的正相关，但在男性患者中没有发现。有趣的是，女性 TSC 患者的致癫痫块茎中 GPR30 表达和 SUVs 显着降低，ROC 曲线表明 SUVs 可以预测致癫痫块茎的定位。总之，我们的结果表明 GPR30 在 FCDIIb 和 TSC 女性患者的癫痫发生中具有潜在的保护作用。