Temporal lobe epilepsy (TLE) development is associated with dysregulation of glutamatergic transmission in the hippocampus; however, detailed molecular mechanisms of pathological changes are still poorly understood. In the present study, we performed the complex analysis of glutamatergic system in the hippocampus of Krushinsky-Molodkina (KM) rats genetically prone to audiogenic seizures (AGS). Daily AGS stimulations (audiogenic kindling) were used to reproduce the dynamics of TLE development. Naïve KM rats were used as a control. After 14 AGS, at the stage of developing TLE, KM rats demonstrated significant upregulation of extracellular signal-regulated kinases (ERK) 1 and 2, cAMP response element-binding protein (CREB), and c-Fos in the hippocampus indicating activation of the hippocampal cells. These changes were accompanied with an increase in glutaminase and vesicular glutamate transporter (VGLUT) 2 suggesting the activation of glutamate production and loading into the synaptic vesicles. After 21 AGS, when TLE was fully-established, alterations were similar but more pronounced, with higher activation of glutaminase, increase in glutamate production, upregulation of VGLUT1 and 2, and Fos-related antigen 1 (Fra-1) along with c-Fos. Analysis of glutamate receptors showed variable changes. Thus, after 14 AGS, simultaneous increase in metabotropic glutamate receptor mGluR1 and decrease in ionotropic N-methyl-D-aspartate (NMDA) receptors could reflect compensatory anti-epileptic mechanism, while further kindling progression induced upregulation of ionotropic receptors, probably, contributing to the hippocampal epileptization. However, we revealed practically no alterations in the expression of synaptic proteins. Altogether, obtained results suggested that overactivation of glutamate production in the hippocampus strongly contributed to TLE development in KM rats.

中文翻译：

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听源引火可激活具有听源性癫痫发作遗传倾向的大鼠海马谷氨酸能系统

颞叶癫痫 (TLE) 的发生与海马谷氨酸能传递失调有关。然而，病理变化的详细分子机制仍然知之甚少。在本研究中，我们对遗传上易发生听源性癫痫发作 (AGS) 的 Krushinsky-Molodkina (KM) 大鼠海马谷氨酸能系统进行了复杂分析。每日 AGS 刺激（发声点燃）用于重现 TLE 发育的动态。使用幼稚 KM 大鼠作为对照。 14 AGS 后，在发展 TLE 的阶段，KM 大鼠表现出海马细胞外信号调节激酶 (ERK) 1 和 2、cAMP 反应元件结合蛋白 (CREB) 和 c-Fos 的显着上调，表明海马细胞。这些变化伴随着谷氨酰胺酶和囊泡谷氨酸转运蛋白 (VGLUT) 2 的增加，表明谷氨酸产生被激活并加载到突触小泡中。 21 AGS 后，当 TLE 完全建立时，变化相似但更明显，谷氨酰胺酶活性更高，谷氨酸产量增加，VGLUT1 和 2 以及 Fos 相关抗原 1 (Fra-1) 和 c- 上调。福斯。谷氨酸受体的分析显示出不同的变化。因此，14 AGS 后，代谢型谷氨酸受体 mGluR1 的同时增加和离子型 N-甲基-D-天冬氨酸 (NMDA) 受体的减少可能反映了代偿性抗癫痫机制，而进一步点燃进展诱导离子型受体的上调，可能有助于海马癫痫。然而，我们发现突触蛋白的表达实际上没有变化。总而言之，获得的结果表明海马谷氨酸生成的过度激活对 KM 大鼠 TLE 的发展有很大影响。