The subiculum represents a crucial brain pivot in regulating seizure generalization in temporal lobe epilepsy (TLE), primarily through synergy of local GABAergic and long-projecting glutamatergic signaling. However, little is known about how subicular GABAergic interneurons are involved in a cell-type-specific way. Here, employing Ca2+ fiber photometry, retrograde monosynaptic viral tracing and chemogenetics in epilepsy models of both male and female mice, we elucidate circuit reorganization patterns mediated by subicular cell-type-specific interneurons and delineate their functional disparities in seizure modulation in TLE. We reveal distinct functional dynamics of subicular parvalbumin+ and somatostatin+ interneurons during secondary generalized seizure. These interneuron subtypes have their biased circuit organizations in terms of both input and output patterns, which undergo distinct reorganization in chronic epileptic condition. Notably, somatostatin+ interneurons exert more effective feedforward inhibition onto pyramidal neurons compared to parvalbumin+ interneurons, which engenders consistent anti-seizure effects in TLE. These findings provide an improved understanding of different subtypes of subicular interneurons in circuit reorganization in TLE, and supplement compelling proofs for precise treatment of epilepsy by targeting subicular somatostatin+ interneurons.Significance statement Temporal lobe epilepsy (TLE) is the most common type of refractory epilepsy and not well controlled by current medications. In this study, we reveal that subicular GABAergic interneurons are involved in seizure generalization in a cell-type-specific way. We find subicular parvalbumin+ and somatostatin+ interneurons have distinct functional dynamics and undergo different circuit reorganizations in chronic epileptic condition. Notably, somatostatin+ interneurons exert more effective inhibition onto pyramidal neurons, engendering consistent anti-seizure effects. This is therapeutically significant for precise treatment targeting the subiculum in TLE.

中文翻译：

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颞叶癫痫中眼下细胞类型特异性中间神经元的回路重组。


颞叶癫痫 （TLE） 中，颞叶下腺素是调节癫痫发作泛义的关键大脑支点，主要是通过局部 GABA 能和长投射谷氨酸能信号传导的协同作用。然而，关于亚型 GABA 能中间神经元如何以细胞类型特异性方式参与，人们知之甚少。在这里，在雄性和雌性小鼠的癫痫模型中采用 Ca 2 + 纤维光度法、逆行单突触病毒示踪和化学遗传学，我们阐明了由下细胞类型特异性中间神经元介导的电路重组模式，并描绘了它们在 TLE 中癫痫发作调节的功能差异。我们揭示了继发性全面性癫痫发作期间小白蛋白 + 和生长抑素 + 中间神经元的不同功能动力学。这些中间神经元亚型在输入和输出模式方面都有其偏倚的回路组织，在慢性癫痫情况下会经历不同的重组。值得注意的是，与小白蛋白 + 中间神经元相比，生长抑素 + 中间神经元对锥体神经元施加更有效的前馈抑制，这在 TLE 中产生一致的抗癫痫作用。这些发现为更好地了解 TLE 回路重组中不同亚型的亚型提供了对 TLE 回路重组的理解，并为通过靶向下生长抑素 + 中间神经元来精确治疗癫痫提供了令人信服的证据。意义陈述 颞叶癫痫 （TLE） 是最常见的难治性癫痫类型，目前的药物不能很好地控制。在这项研究中，我们揭示了皮下 GABA 能中间神经元以细胞类型特异性方式参与癫痫发作泛化。 我们发现眼下小白蛋白 + 和生长抑素 + 中间神经元具有不同的功能动力学，并在慢性癫痫情况下经历不同的回路重组。值得注意的是，生长抑素 + 中间神经元对锥体神经元施加更有效的抑制，产生一致的抗癫痫作用。这对于针对 TLE 中 subiculum 的精确治疗具有治疗意义。