LATERAL CEREBELLAR NUCLEUS (LCN) CONTRIBUTION TO MYOCLONUS PATHOGENESIS IN PTZ-KINDLED RATS

In recent years, the cerebellum and its nuclei have become an essential target for understanding and suppressing the mechanisms of seizures. Тus, Kros et al. (2015) reported that cerebellar nuclei are potent modulators of thalamocortical network pathological oscillations observed during generalized spike-wave discharges (SWDs) generation. Accordingly, cerebellar nuclei neurons can be identified as therapeutic targets, especially in controlling absence seizures (Kros et al. 2015). Another study showed that single-pulse optogenetic stimulation of cerebellar nuclei disrupted neuronal thalamic oscillations during SWD generation (Rooda et al., 2021).
Cerebellar crosstalk with forebrain epileptic activity has been well-documented since the sixteenth of the previous century, with a wide range of data showing both suppressive and facilitative characteristics (Akyuz et al., 2021; Zangiabadi et al., 2019; Beckinghausen et al., 2023). Hence, the next steps in clarifying factors contributing to data controversies and the role of cerebellar structures in seizure control are necessary.
This investigation aims to observe the EEG and behavioral peculiarities of PTZ-kindled manifestations with an emphasis on myoclonus seizure, at early and fully developed stages under LCN electrical stimulation (ES) conditions.
The male Wistar rats were kindled with pentylenetetrazol (PTZ) (35.0 mg/kg, i.p.) to myoclonus (9-11 PTZ injections) and generalized tonic-clonic seizures (21 PTZ injections). Unilateral ES (100 Hz) was delivered daily for five days after the last kindled PTZ administration, with PTZ seizure testing after ES. Seizures were videotaped, and the severity score was determined in a blinded manner.
ES of LCN performed at the early stage of kindling facilitated the appearance of myoclonus and increased seizure severity by 30.2% points compared to the control group (H=6.567; p = 0.037) with the spikes frequency generation during the poststimulation period (F(5,42)=15.41, p < 0.001). In fully developed kindling, ES prevented generalized seizure and reduced seizure severity by 27.5% (H=11.058; p = 0.004), while myoclonuses were present with spikes generation in brain structures.
The data obtained showed that repeated ES of LCN at the early stage promoted myoclonic seizures, while in fully PTZ-kindled rats, it suppressed generalized seizure fits, which were substituted with myoclonus. Hence, LCN activity might be facilitative for seizure myoclonus precipitation while suppressive for spreading generalized activity in wider neuronal networks.

近年来，小脑及其核团已成为理解并抑制癫痫发作机制的关键靶点。据此，Kros 等人（2015 年）指出，小脑核团是调节在弥漫性棘波放电（SWDs）产生过程中观察到的丘脑皮层网络病理性振荡的强效调节因子。因此，小脑核团神经元可被识别为治疗靶点，尤其是在控制失神癫痫方面（Kros 等人，2015 年）。另一项研究显示，对 cerebellar nuclei 的单脉冲光遗传学刺激可中断 SWD 产生过程中的神经元丘脑振荡（Rooda 等人，2021 年）。自上个世纪十六世纪以来，小脑与大脑皮层癫痫活动的交叉对话已被广泛记录，大量数据显示了抑制性和促进性特征的并存（Akyuz 等人，2021 年；Zangiabadi 等人，2019 年；Beckinghausen 等人，2023 年）。因此，澄清导致数据争议的因素以及小脑结构在癫痫控制中的作用成为必要步骤。本研究旨在观察在 LCN 电刺激（ES）条件下，PTZ 诱导表现中肌阵挛癫痫的 EEG 和行为特性，重点关注早期和完全发展阶段。雄性 Wistar 大鼠经戊四氮（PTZ）（35.0 mg/kg，i.p.）诱导产生肌阵挛（9-11 次PTZ 注射）和全身性强直阵挛性癫痫（21 次PTZ 注射）。在最后一次 PTZ 诱导后，每日进行单侧 ES（100 Hz）刺激五天，并在 ES 后进行 PTZ 癫痫测试。癫痫发作被录像，严重程度评分以盲法进行。在诱导早期，LCN 的 ES 刺激促进了肌阵挛的出现，与对照组相比，增加了 30.2% 的癫痫严重程度（H=6.567；p = 0.037），在刺激后期间产生了尖峰频率（F(5,42)=15.41，p < 0.001）。在完全诱导阶段，ES 预防了全身性癫痫发作，将癫痫严重程度降低了 27.5%（H=11.058；p = 0.004），而肌阵挛仍然存在，大脑结构中产生了尖峰。获得的数据表明，在诱导早期重复 LCN 的 ES 刺激促进了肌阵挛性癫痫，而在完全 PTZ 诱导的大鼠中，它抑制了全身性癫痫发作，这些发作被肌阵挛所取代。因此，LCN 活动可能有利于肌阵挛性癫痫的诱发，而对更广泛神经元网络中扩散的全身性活动具有抑制作用。