内侧颞叶癫痫（MTLE）是最常见的药物难治性癫痫。申请人前期发现抑制Hsp90可降低致癫灶的谷氨酸浓度，具有显著的抗癫痫效果，但尚不能达到完全缓解。我们推测可能与未得到改善的神经环路异常重组有关。在此基础上，本研究将重点阐明谷氨酸与mTOR通路的相互作用在致癫灶神经元轴树突异常重组中的作用机制，并找到合适的mTOR通路小分子抑制剂，与可口服的低毒性Hsp90抑制剂联合使用，同时降低致癫灶的谷氨酸浓度并改善神经环路异常重组的病理表型。利用啮齿类和非人灵长类MTLE模型（食蟹猴模型），证实组合疗法具有更强的抗癫痫效果，并能缓解部分致癫灶的病理表型。本研究若能取得预期结果，将为开发难治性癫痫的药物治疗方法提供新的思路和理论依据。

Mesial temporal lobe epilepsy (MTLE) is the most common type of drug-resistant epilepsy. We previously demonstrated that inhibition of Hsp90 to reduce glutamate levels produced significant antiepileptic effects, but the animals still can not achieve complete seizure control. We assume that the unimproved reorganization of abnormal neural circuits is the underlying reason. In this study, we aim to (1) screen orally bioavailable Hsp90 with minimal toxicity inhibitors as candidate antiepileptic drugs, and (2) investiagate the role of molecular interaction between glutamate and the mTOR pathway in developing excessive neurites outgrowth. With the combination of chemical inhibitors of the mTOR pathway molecule and Hsp90, we can simultaneously reduce glutamate levels and ameliorate reorganization of abnormal neural circuits in the sclerotic hippocampus. By using rodent and non-human primate models of MTLE, we will explore whether this combination therapy is a better way to treat MTLE. If experimental evidence supports our hypothesis, it will provides new ideas and theoretical basis to further develop drugs and treatment methods for drug-resistant epilepsy.