The persistent unresponsiveness of many of the acquired epilepsies to traditional antiseizure medications has motivated the search for prophylactic drug therapies that could reduce the incidence of epilepsy in this at risk population. These studies are based on the idea of a period of epileptogenesis that can follow a wide variety of brain injuries. Epileptogenesis is hypothesized to involve changes in the brain not initially associated with seizures, but which result finally in seizure prone networks. Understanding these changes will provide crucial clues for the development of prophylactic drugs. Using the repeated low-dose kainate rat model of epilepsy, we have studied the period of epileptogenesis following status epilepticus, verifying the latent period with continuous EEG monitoring. Focusing on ultrastructural properties of the tripartite synapse in the CA1 region of hippocampus we found increased astrocyte ensheathment around both the presynaptic and postsynaptic elements, reduced synaptic AMPA receptor subunit and perisynaptic astrocyte GLT-1 expression, and increased number of docked vesicles at the presynaptic terminal. These findings were associated with an increase in frequency of the mEPSCs observed in patch clamp recordings of CA1 pyramidal cells. The results suggest a complex set of changes, some of which have been associated with increasingly excitable networks such as increased vesicles and mEPSC frequency, and some associated with compensatory mechanisms, such as increased astrocyte ensheathment. The diversity of ultrastructural and electrophysiological changes observed during epileptogeneiss suggests that potential drug targets for this period should be broadened to include all components of the tripartite synapse.

中文翻译：

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在颞叶癫痫模型的癫痫发生过程中，三方突触的超微结构和功能变化。

许多获得性癫痫对传统抗癫痫药物的持续无反应性促使人们寻求预防药物疗法，以减少这种高危人群中癫痫的发生率。这些研究基于癫痫发生时期的想法，该时期可能会导致多种脑损伤。据推测，癫痫发生涉及大脑的变化，这些变化最初与癫痫发作无关，但最终导致易发作的网络。了解这些变化将为预防药物的开发提供重要线索。使用重复的小剂量海藻酸盐大鼠模型，我们研究了癫痫持续状态后的癫痫发生期，并通过连续的脑电图监测来验证潜伏期。着眼于海马CA1区的三重突触的超微结构特性，我们发现突触前和突触后元件周围的星形胶质细胞鞘增多，突触AMPA受体亚基和突触周围星形胶质细胞GLT-1表达减少，以及突触前末端停靠的囊泡数量增加。这些发现与在CA1锥体细胞的膜片钳记录中观察到的mEPSC频率增加有关。结果表明，存在一系列复杂的变化，其中一些变化与越来越兴奋的网络相关，例如增加的囊泡和mEPSC频率，而另一些变化与补偿机制相关，例如星形胶质细胞的包埋增加。