星形胶质细胞连接蛋白的组成性缺失会加重红藻氨酸诱发的癫痫。,Glia

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星形胶质细胞连接蛋白的组成性缺失会加重红藻氨酸诱发的癫痫。
Glia ( IF 5.4 ) Pub Date : 2020-04-02 , DOI: 10.1002/glia.23832
Tushar Deshpande ₁ , Tingsong Li ₂ , Lukas Henning ₁ , Zhou Wu ₁ , Julia Müller ₁ , Gerald Seifert ₁ , Christian Steinhäuser ₁ , Peter Bedner ₁

Affiliation

由连接蛋白 (Cx) 通道形成的星形胶质间隙连接网络在调节神经元活动和网络同步方面起着核心作用。然而，尚不了解其参与癫痫的发生和进展。在内侧颞叶癫痫 (MTLE) 患者的硬化海马体和 MTLE 小鼠模型中观察到星形细胞间隙连接 (GJ) 偶联缺失，这表明它在发病机制中起致病作用。为了进一步阐明这一临床相关问题，我们通过将星形胶质细胞 Cx 蛋白缺陷的小鼠与野生型小鼠 (WT) 进行比较，研究了星形胶质细胞断开对海马酸盐诱导的海马硬化症 (HS) MTLE 的时间进程和严重程度的影响。癫痫持续状态没有什么不同。免疫组织化学分析表明，尽管慢性癫痫活动升高，星形胶质细胞的断开并未加重 HS 的严重程度。实际上，实验组之间 CA1 锥体细胞损失的程度相似，而与 WT 小鼠相比，Cx 缺陷小鼠的星形胶质细胞增生、颗粒细胞分散、血管生成和小胶质细胞活化甚至减少。有趣的是，成年齿状回中癫痫引起的神经发生也与星形细胞 Cxs 无关。总之，我们的数据表明星形胶质细胞之间 GJ 耦合的组成性丧失促进了神经元过度兴奋并减弱了癫痫引起的组织病理学结果。

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Constitutive deletion of astrocytic connexins aggravates kainate-induced epilepsy.

The astroglial gap junctional network formed by connexin (Cx) channels plays a central role in regulating neuronal activity and network synchronization. However, its involvement in the development and progression of epilepsy is not yet understood. Loss of interastrocytic gap junction (GJ) coupling has been observed in the sclerotic hippocampus of patients with mesial temporal lobe epilepsy (MTLE) and in mouse models of MTLE, leading to the suggestion that it plays a causative role in the pathogenesis. To further elucidate this clinically relevant question, we investigated consequences of astrocyte disconnection on the time course and severity of kainate‐induced MTLE with hippocampal sclerosis (HS) by comparing mice deficient for astrocytic Cx proteins with wild‐type mice (WT). Continuous telemetric EEG recordings and video monitoring performed over a period of 4 weeks after epilepsy induction revealed substantially higher seizure and interictal spike activity during the chronic phase in Cx deficient versus WT mice, while the severity of status epilepticus was not different. Immunohistochemical analysis showed that, despite the elevated chronic seizure activity, astrocyte disconnection did not aggravate the severity of HS. Indeed, the extent of CA1 pyramidal cell loss was similar between the experimental groups, while astrogliosis, granule cell dispersion, angiogenesis, and microglia activation were even reduced in Cx deficient as compared to WT mice. Interestingly, seizure‐induced neurogenesis in the adult dentate gyrus was also independent of astrocytic Cxs. Together, our data indicate that constitutive loss of GJ coupling between astrocytes promotes neuronal hyperexcitability and attenuates seizure‐induced histopathological outcomes.

更新日期：2020-04-02

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