Multiple Disruptions of Glial-Neuronal Networks in Epileptogenesis That Follows Prolonged Febrile Seizures.
Multiple Disruptions of Glial-Neuronal Networks in Epileptogenesis That Follows Prolonged Febrile Seizures.
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DOI：
10.3389/fneur.2021.615802
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发表时间：
2021
影响因子：
3.4
通讯作者：
Baram TZ
中科院分区：
文献类型：
--
作者：
Brennan GP;Garcia-Curran MM;Patterson KP;Luo R;Baram TZ
背景和依据：双向神经元-胶质细胞通讯是正常脑功能的关键介质，在癫痫脑中被破坏。异常小胶质细胞和星形胶质细胞功能在癫痫发生过程中的潜在作用是重要的，因为所涉及的介质为干预和预防癫痫提供了切实的靶点。胶质细胞活化与儿童期热性惊厥（FS）的发生密切相关，而长期的FS（febrile status epilepticus，FSE）是成年期颞叶癫痫（TLE）的发病基础。由于TLE通常难以治疗，并伴有显著的记忆和情感困难，我们探讨了实验性FSE（eFSE）后癫痫发生中神经胶质-神经元网络中断的作用。研究方法：我们进行了多管齐下的检查神经元-胶质细胞通信，并在这些细胞类型的eFSE后，在未成熟的小鼠和大鼠的分子信号级联的激活。具体而言，我们研究了涉及细胞因子，microRNA，高迁移率族B-1（HMGB 1）和前列腺素E2信号传导的途径。我们的目的是使用网络特异性干预以及通过使用地塞米松的整体抗炎方法来阻断癫痫发生。结果：（A）eFSE引起强烈的炎症反应，伴随促炎细胞因子的快速和持续上调。(B)在eFSE结束的几分钟内，HMGB 1从神经元核转移到树突，途中到达细胞外空间和胶质细胞Toll样受体。对eFSE大鼠幼仔施用HMGB 1阻断剂不会降低下游炎症级联的表达，并导致不可接受的副作用。(C)长时间的海马样活性导致海马体中总体microRNA-124（miR-124）水平骤降，并通过细胞外囊泡从神经元释放这种microRNA。(D)在eFSE的数小时内，结构性星形胶质细胞和小胶质细胞的活化不仅与细胞因子的产生有关，而且与PGE 2级联的活化有关。然而，给予TG 6 -10-1（一种PGE 2受体EP 2的阻断剂）对eFSE引起的尖峰系列几乎没有影响。(E)与选择性干预的失败相反，用广泛的抗炎药地塞米松对经历eFSE的大鼠幼崽进行3天治疗，减弱了eFSE引起的促癫痫EEG变化。结论：eFSE是啮齿类动物中TLE样癫痫的诱发物，导致相互连接的胶质神经元网络的多次和快速破坏，在癫痫发生中可能具有重要作用。这些网络之间复杂的、细胞特异性的和稳态的相互作用对旨在预防癫痫的有效选择性干预构成了严重挑战。相反，广泛抑制胶质神经元功能障碍有望减轻FSE诱导的过度兴奋和癫痫发生在实验模型和人类。
Background and Rationale: Bi-directional neuronal-glial communication is a critical mediator of normal brain function and is disrupted in the epileptic brain. The potential role of aberrant microglia and astrocyte function during epileptogenesis is important because the mediators involved provide tangible targets for intervention and prevention of epilepsy. Glial activation is intrinsically involved in the generation of childhood febrile seizures (FS), and prolonged FS (febrile status epilepticus, FSE) antecede a proportion of adult temporal lobe epilepsy (TLE). Because TLE is often refractory to treatment and accompanied by significant memory and emotional difficulties, we probed the role of disruptions of glial-neuronal networks in the epileptogenesis that follows experimental FSE (eFSE). Methods: We performed a multi-pronged examination of neuronal-glia communication and the resulting activation of molecular signaling cascades in these cell types following eFSE in immature mice and rats. Specifically, we examined pathways involving cytokines, microRNAs, high mobility group B-1 (HMGB1) and the prostaglandin E2 signaling. We aimed to block epileptogenesis using network-specific interventions as well as via a global anti-inflammatory approach using dexamethasone. Results: (A) eFSE elicited a strong inflammatory response with rapid and sustained upregulation of pro-inflammatory cytokines. (B) Within minutes of the end of the eFSE, HMGB1 translocated from neuronal nuclei to dendrites, en route to the extracellular space and glial Toll-like receptors. Administration of an HMGB1 blocker to eFSE rat pups did not decrease expression of downstream inflammatory cascades and led to unacceptable side effects. (C) Prolonged seizure-like activity caused overall microRNA-124 (miR-124) levels to plunge in hippocampus and release of this microRNA from neurons via extra-cellular vesicles. (D) Within hours of eFSE, structural astrocyte and microglia activation was associated not only with cytokine production, but also with activation of the PGE2 cascade. However, administration of TG6-10-1, a blocker of the PGE2 receptor EP2 had little effect on spike-series provoked by eFSE. (E) In contrast to the failure of selective interventions, a 3-day treatment of eFSE–experiencing rat pups with the broad anti-inflammatory drug dexamethasone attenuated eFSE-provoked pro-epileptogenic EEG changes. Conclusions: eFSE, a provoker of TLE-like epilepsy in rodents leads to multiple and rapid disruptions of interconnected glial-neuronal networks, with a likely important role in epileptogenesis. The intricate, cell-specific and homeostatic interplays among these networks constitute a serious challenge to effective selective interventions that aim to prevent epilepsy. In contrast, a broad suppression of glial-neuronal dysfunction holds promise for mitigating FSE-induced hyperexcitability and epileptogenesis in experimental models and in humans.
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在慢性颞叶癫痫大鼠模型中，前脑细胞外囊泡显示 miR-346 和 miR-331-3p 减少。
影响因子：
5.1
作者：
Gitaí DLG;Dos Santos YDR;Upadhya R;Kodali M;Madhu LN;Shetty AK
通讯作者：
Shetty AK
影响因子：
6.1
作者：
Duffy BA;Chun KP;Ma D;Lythgoe MF;Scott RC
通讯作者：
Scott RC
DOI：
10.1523/jneurosci.0558-12.2012
发表时间：
2012-06-27
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Åkerblom M;Sachdeva R;Barde I;Verp S;Gentner B;Trono D;Jakobsson J
通讯作者：
Jakobsson J
影响因子：
5.3
作者：
Brewster, A;Bender, RA;Baram, TZ
通讯作者：
Baram, TZ
影响因子：
4.3
作者：
Batool, Aasia;Hill, Thomas D. M.;Henshall, David C.
通讯作者：
Henshall, David C.