Overexpression of Slit2 decreases neuronal excitotoxicity, accelerates glymphatic clearance, and improves cognition in a multiple microinfarcts model.
Overexpression of Slit2 decreases neuronal excitotoxicity, accelerates glymphatic clearance, and improves cognition in a multiple microinfarcts model.
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Slit2 的过度表达可降低神经元兴奋性毒性，加速类淋巴清除，并改善多发性微梗死模型中的认知
DOI：
10.1186/s13041-020-00659-5
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发表时间：
2020-10-07
期刊：
影响因子：
3.6
通讯作者：
Hu XQ
中科院分区：
文献类型：
--
作者：
He XF;Li G;Li LL;Li MY;Liang FY;Chen X;Hu XQ
脑微梗死（MIs）会导致老年人进行性认知障碍，由于其潜在致病机制尚不明确，目前尚无有效的预防策略。一种可能性是γ-氨基丁酸（GABA）能传递功能障碍及随之而来的兴奋毒性。GABA能传递功能障碍会诱发兴奋毒性，这与中风病理相关，但其机制仍不明确。分泌型富含亮氨酸重复序列（LRR）家族蛋白Slit同源物2（Slit2）可上调GABA能活性，并对全脑缺血起到保护作用，但Slit2对脑微梗死的神经保护效果尚未得到研究。
将中年野生型（WT）和Slit2转基因小鼠分为假手术组和脑微梗死治疗组。通过激光诱发小动脉闭塞在顶叶皮质诱导脑微梗死。然后使用莫里斯水迷宫（MWM）实验比较假手术组和脑微梗死组的空间记忆能力。此外，利用双光子成像比较梗死灶周围区域的神经元活动、血脑屏障（BBB）通透性和类淋巴清除功能，同时通过免疫荧光染色或蛋白质免疫印迹法比较GABA能传递、小胶质细胞激活、神经元丢失以及皮质连接改变情况。
脑微梗死增加了自发细胞内Ca2+信号的幅度和频率，降低了顶叶皮质内神经元的存活率和连接性，减少了GABA能中间神经元的数量以及囊泡GABA转运体（VGAT）的表达，诱发了神经炎症，并损害了类淋巴清除功能和空间记忆能力。相反，Slit2过表达减弱了神经元Ca2+信号的功能障碍，保护梗死灶周围区域的神经元免于死亡以及顶叶皮质连接性的丧失，增加了GABA能中间神经元的数量和VGAT的表达，减轻了神经炎症，并改善了类淋巴清除功能和空间记忆能力。
我们的研究结果有力地表明，Slit2过表达可预防脑微梗死中的功能障碍，这是治疗老年人认知障碍的一个潜在治疗靶点。
BackgroundCerebral microinfarcts (MIs) lead to progressive cognitive impairments in the elderly, and there is currently no effective preventative strategy due to uncertainty about the underlying pathogenic mechanisms. One possibility is the dysfunction of GABAergic transmission and ensuing excitotoxicity. Dysfunction of GABAergic transmission induces excitotoxicity, which contributes to stroke pathology, but the mechanism has kept unknown. The secreted leucine-rich repeat (LRR) family protein slit homologue 2 (Slit2) upregulates GABAergic activity and protects against global cerebral ischemia, but the neuroprotective efficacy of Slit2 against MIs has not been examined.MethodsMiddle-aged Wild type (WT) andSlit2-Tgmice were divided into sham and MI treatment groups. MIs were induced in parietal cortex by laser-evoked arteriole occlusion. Spatial memory was then compared between sham and MI groups using the Morris water maze (MWM) task. In addition, neuronal activity, blood brain barrier (BBB) permeability, and glymphatic clearance in peri-infarct areas were compared using two-photon imaging, while GABAergic transmission, microglial activation, neuronal loss, and altered cortical connectivity were compared by immunofluorescent staining or western blotting.ResultsMicroinfarcts increased the amplitude and frequency of spontaneous intracellular Ca2+signals, reduced neuronal survival and connectivity within parietal cortex, decreased the number of GABAergic interneurons and expression of vesicular GABA transporter (VGAT), induced neuroinflammation, and impaired both glymphatic clearance and spatial memory. Alternatively, Slit2 overexpression attenuated dysfunctional neuronal Ca2+signaling, protected against neuronal death in the peri-infarct area as well as loss of parietal cortex connectivity, increased GABAergic interneuron number and VGAT expression, attenuated neuroinflammation, and improved both glymphatic clearance and spatial memory.ConclusionOur results strongly suggest that overexpression of Slit2 protected against the dysfunction in MIs, which is a potential therapeutic target for cognition impairment in the elderly.
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影响因子：
64.5
作者：
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通讯作者：
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