Proskurina Elena Yu, Ergina Julia L, Zaitsev Aleksey V
Laboratory of Molecular Mechanisms of Neural Interactions, Sechenov Institute of Evolutionary Physiology and Biochemistry of RAS, 194223 Saint Petersburg, Russia.
Int J Mol Sci. 2025 Jul 16;26(14):6812. doi: 10.3390/ijms26146812.
The mechanisms of ictal discharge initiation remain incompletely understood, particularly the paradoxical role of inhibitory fast-spiking interneurons in seizure generation. Using simultaneous whole-cell recordings of interneurons and pyramidal neurons combined with extracellular [K] monitoring in mouse entorhinal cortex-hippocampal slices (4-aminopyridine model of epileptiform activity), we identified a critical transition sequence: interneurons displayed high-frequency firing during the preictal phase before entering depolarization block (DB). DB onset coincided with the peak of rate of extracellular [K] accumulation. Pyramidal cells remained largely silent during interneuronal hyperactivity but started firing within 1.1 ± 0.3 s after DB onset, marking the transition to ictal discharges. This consistent sequence (interneuron DB → [K] rate peak → pyramidal cell firing) was observed in 100% of entorhinal cortex recordings. Importantly, while neurons across all entorhinal cortical layers synchronously fired during the first ictal discharge, hippocampal CA1 neurons showed fundamentally different activity: they generated high-frequency interictal bursts but did not participate in ictal events, indicating region-specific seizure initiation mechanisms. Our results demonstrate that interneuron depolarization block acts as a precise temporal switch for ictogenesis and suggest that the combined effect of disinhibition and K-mediated depolarization triggers synchronous pyramidal neuron recruitment. These findings provide a mechanistic framework for seizure initiation in focal epilepsy, highlighting fast-spiking interneurons dysfunction as a potential therapeutic target.
癫痫发作起始的机制仍未完全明了，尤其是抑制性快发放中间神经元在癫痫发作产生中所起的矛盾作用。在小鼠内嗅皮层-海马切片（癫痫样活动的4-氨基吡啶模型）中，我们通过同时对中间神经元和锥体细胞进行全细胞膜片钳记录并结合细胞外[K]监测，确定了一个关键的转变序列：在进入去极化阻滞（DB）之前的发作前期，中间神经元呈现高频放电。DB的起始与细胞外[K]积累速率的峰值一致。在中间神经元活动亢进期间，锥体细胞基本保持沉默，但在DB起始后1.1±0.3秒内开始放电，标志着向癫痫发作放电的转变。在100%的内嗅皮层记录中都观察到了这种一致的序列（中间神经元DB→[K]速率峰值→锥体细胞放电）。重要的是，虽然在首次癫痫发作放电期间，所有内嗅皮层层的神经元同步放电，但海马CA1神经元表现出根本不同的活动：它们产生高频发作间期爆发，但不参与癫痫发作事件，这表明存在区域特异性的癫痫发作起始机制。我们的结果表明，中间神经元去极化阻滞作为癫痫发生的精确时间开关，提示去抑制和K⁺介导的去极化的联合作用触发了锥体细胞的同步募集。这些发现为局灶性癫痫的发作起始提供了一个机制框架，突出了快发放中间神经元功能障碍作为一个潜在的治疗靶点。
