Preferential pruning of inhibitory synapses by microglia contributes to alteration of the balance between excitatory and inhibitory synapses in the hippocampus in temporal lobe epilepsy.
Preferential pruning of inhibitory synapses by microglia contributes to alteration of the balance between excitatory and inhibitory synapses in the hippocampus in temporal lobe epilepsy.
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DOI：
10.1111/cns.14224
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发表时间：
2023-10
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
颞叶癫痫（TLE）的发病机制与脑内的神经回路有关，这已成为共识。特别是，突触兴奋/抑制平衡（E/I平衡）已涉及在TLE的发展过程中向兴奋升高的转变。SD大鼠腹腔注射海人酸（KA）建立颞叶癫痫（TLE）模型。接着，应用脑电图（EEG）记录来验证大鼠自发性反复发作（SRS）的稳定性和可检测性。此外，从大鼠和内侧颞叶癫痫（mTLE）患者的海马切片进行了评估，使用免疫荧光法，以确定兴奋性和抑制性突触和小胶质细胞吞噬功能的改变。我们发现，KA诱导稳定的SRS癫痫持续状态（SE）发作后14天。此外，我们发现在癫痫发生过程中兴奋性突触的持续增加，其中囊泡谷氨酸转运蛋白1（vGluT 1）的总面积在角氨1（CA 1）的放射层（SR），CA 3的透明层（SL）和齿状回（DG）的多形层（PML）中显著上升。相反，抑制性突触显著减少，SL和PML中谷氨酸脱羧酶65（GAD 65）的总面积大大减少。此外，小胶质细胞在SRS形成后进行了活跃的突触吞噬，尤其是在SL和PML中。最后，在大鼠和人海马脑片中，小胶质细胞在反复发作期间优先修剪抑制性突触，这有助于海马亚区的突触改变。我们的研究结果详细描述了TLE中神经回路的改变，并证明了小胶质细胞介导的突触吞噬作用的选择性，这将有助于加深对TLE发病机制的理解，并为癫痫治疗提供潜在的治疗靶点。在海马的TLE回路相关的子区域中，兴奋性突触的数量增加，而抑制性突触减少。癫痫形成后，小胶质细胞大量激活，尤其是透明层和多形层，进行吞噬作用。在TLE中，小胶质细胞优先修剪海马中的抑制性突触。
A consensus has formed that neural circuits in the brain underlie the pathogenesis of temporal lobe epilepsy (TLE). In particular, the synaptic excitation/inhibition balance (E/I balance) has been implicated in shifting towards elevated excitation during the development of TLE. Sprague Dawley (SD) rats were intraperitoneally subjected to kainic acid (KA) to generate a model of TLE. Next, electroencephalography (EEG) recording was applied to verify the stability and detectability of spontaneous recurrent seizures (SRS) in rats. Moreover, hippocampal slices from rats and patients with mesial temporal lobe epilepsy (mTLE) were assessed using immunofluorescence to determine the alterations of excitatory and inhibitory synapses and microglial phagocytosis. We found that KA induced stable SRSs 14 days after status epilepticus (SE) onset. Furthermore, we discovered a continuous increase in excitatory synapses during epileptogenesis, where the total area of vesicular glutamate transporter 1 (vGluT1) rose considerably in the stratum radiatum (SR) of cornu ammonis 1 (CA1), the stratum lucidum (SL) of CA3, and the polymorphic layer (PML) of the dentate gyrus (DG). In contrast, inhibitory synapses decreased significantly, with the total area of glutamate decarboxylase 65 (GAD65) in the SL and PML diminishing enormously. Moreover, microglia conducted active synaptic phagocytosis after the formation of SRSs, especially in the SL and PML. Finally, microglia preferentially pruned inhibitory synapses during recurrent seizures in both rat and human hippocampal slices, which contributed to the synaptic alteration in hippocampal subregions. Our findings elaborately characterize the alteration of neural circuits and demonstrate the selectivity of synaptic phagocytosis mediated by microglia in TLE, which could strengthen the comprehension of the pathogenesis of TLE and inspire potential therapeutic targets for epilepsy treatment. In TLE circuit‐related subregions of the hippocampus, the number of excitatory synapses increased, while inhibitory synapses decreased during epileptogenesis. Microglia activated in a considerable number after epilepsy has formed, especially in stratum lucidum and polymorphic layer, which conducted phagocytosis. In TLE, microglia preferentially pruned inhibitory synapses in the hippocampus.
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影响因子：
3
作者：
Huberfeld G;Blauwblomme T;Miles R
通讯作者：
Miles R
影响因子：
16.6
作者：
Absalom NL;Liao VWY;Johannesen KMH;Gardella E;Jacobs J;Lesca G;Gokce-Samar Z;Arzimanoglou A;Zeidler S;Striano P;Meyer P;Benkel-Herrenbrueck I;Mero IL;Rummel J;Chebib M;Møller RS;Ahring PK
通讯作者：
Ahring PK
DOI：
10.1177/0271678x21999553
发表时间：
2021-09
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
Chandra PK;Cikic S;Baddoo MC;Rutkai I;Guidry JJ;Flemington EK;Katakam PV;Busija DW
通讯作者：
Busija DW
影响因子：
5.3
作者：
Avignone, Elena;Ulmann, Lauriane;Audinat, Etienne
通讯作者：
Audinat, Etienne
影响因子：
2.5
作者：
Alhourani, Ahmad;Fish, Kenneth N.;Richardson, R. Mark
通讯作者：
Richardson, R. Mark