难治性颞叶癫痫成因复杂，迄今缺乏合适的药物靶点和治疗策略。申请人的前期研究发现低频率电刺激海马下托可以逆转耐药，提示下托可能与难治性癫痫形成有关。进一步的预实验利用在体微电极阵列记录研究发现，抗癫痫药苯妥英钠无法抑制难治性癫痫模型下托的谷氨酸能神经元的活性，在非耐药癫痫动物中，利用光遗传学技术特异性激活下托谷氨酸能神经元可以诱导出耐药现象。这些初步的结果提示药物对下托谷氨酸能神经元的作用失常可能介导难治性颞叶癫痫的形成机制，下托谷氨酸能神经元可能是精准治疗难治性癫痫的潜在靶点。因此本课题拟利用电生理、光和药物遗传学、药理学、影像学等方法，明确和阐明海马下托谷氨酸能神经元对难治性癫痫形成的作用，为临床精准治疗难治性癫痫提供潜在药物靶点和新的策略。

The mechanism of refractory temporal lobe epilepsy is complex, and lacks effective treatment strategy and drug target. Our previous study found that low frequency stimulation at subiculum can reverse the drug-resistant state, which suggests that subiculum might be correlated with the genesis of refractory temporal lobe epilepsy. Further we used micro electrode array recording in vivo and found that phenytoin cannot inhibit the firing of subicular glutamatergic neurons in drug-resistant rat. In drug-response rats, selective activation of subicular glutamatergic neurons by optogenetics can induce drug-resistant state. All these preliminary results suggest that subicular glutamatergic neurons might mediate the genesis of refractory temporal lobe epilepsy. Thus we will use methods of electrophysiology, optogenetics, chemogenetics, pharmacology and iconography to further clarify the relationship of subicular glutamatergic neurons and refractory temporal lobe epilepsy, and to find the potential target for precise treatment in the future.