Secondary epileptogenesis is characterized by increased epileptic susceptibility and a tendency to generate epileptiform activities outside the primary focus. It is one of the major resultants of pharmacoresistance and failure of surgical outcomes in epilepsy, but still lacks effective treatments. Here, we aimed to test the effects of low-frequency stimulation (LFS) at the subiculum for secondary epileptogenesis in a mouse model. Here, secondary epileptogenesis was simulated at regions both contralateral and ipsilateral to the primary focus by applying successive kindling stimuli. Mice kindled at the right CA3 showed higher seizure susceptibilities at both the contralateral CA3 and the ipsilateral entorhinal cortex and had accelerated kindling processes compared with naive mice. LFS at the ipsilateral subiculum during the primary kindling progress at the right CA3 effectively prevented secondary epileptogenesis at both the contralateral CA3 and the ipsilateral entorhinal cortex, characterized by decreased seizure susceptibilities and a retarded kindling process at those secondary foci. Only application along with the primary epileptogenesis was effective. Notably, the effects of LFS on secondary epileptogenesis were associated with its inhibitory effect at the secondary focus through interfering with the enhancement of synaptic connections between the primary and secondary foci. These results imply that LFS at the subiculum is an effective preventive strategy for extensive secondary epileptogenesis in temporal lobe epilepsy and present the subiculum as a target with potential translational importance.

继发性癫痫发生的特点是癫痫易感性增加，并且倾向于在原发病灶之外产生癫痫样活动。它是癫痫药物耐药性和手术失败的主要原因之一，但仍缺乏有效的治疗方法。在这里，我们的目的是在小鼠模型中测试下托低频刺激（LFS）对继发性癫痫发生的影响。在这里，通过施加连续的点燃刺激，在主要病灶的对侧和同侧区域模拟继发性癫痫发生。与初始小鼠相比，在右侧 CA3 点燃的小鼠在对侧 CA3 和同侧内嗅皮层均表现出更高的癫痫发作敏感性，并且加速了点燃过程。在右侧 CA3 的初级点燃过程中，同侧下托的 LFS 有效地防止了对侧 CA3 和同侧内嗅皮层的继发性癫痫发生，其特征是癫痫易感性降低和这些次级病灶的点燃过程延迟。只有与原发性癫痫发生一起应用才有效。值得注意的是，LFS 对继发性癫痫发生的影响与其通过干扰初级病灶和次级病灶之间突触连接的增强而对次级病灶的抑制作用相关。这些结果表明，下托的 LFS 是颞叶癫痫广泛继发性癫痫发生的有效预防策略，并将下托作为具有潜在转化重要性的靶点。