Cerebral 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. Middle-aged Wild type (WT) and Slit2-Tg mice 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. Microinfarcts 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. Our 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.

中文翻译：

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Slit2的过表达降低了神经元兴奋性毒性，加速了淋巴清除，并改善了多发性微梗塞模型中的认知

脑微梗塞（MIs）会导致老年人进行性认知障碍，由于潜在的致病机制尚不确定，目前尚无有效的预防策略。一种可能性是GABA能传递的功能障碍和随之而来的兴奋性毒性。GABA能传递的功能障碍会诱发兴奋性毒性，这是导致中风病理的原因，但其机制尚不清楚。分泌的富含亮氨酸的重复序列（LRR）家族蛋白狭缝同源物2（Slit2）上调GABA能活性并防止整体脑缺血，但尚未检查Slit2对MI的神经保护作用。将野生野生型（WT）和Slit2-Tg小鼠分为假手术和MI治疗组。激光诱发的小动脉阻塞在顶叶皮层中诱发MI。然后使用莫里斯水迷宫（MWM）任务比较假手术组和MI组之间的​​空间记忆。此外，使用双光子成像比较了梗死周围区域的神经元活动，血脑屏障（BBB）通透性和淋巴结清除率，而免疫荧光染色或免疫荧光法比较了GABA能传递，小胶质细胞活化，神经元丢失和皮质连接改变蛋白质印迹。微梗塞增加了自发性细胞内Ca2 +信号的幅度和频率，降低了顶叶皮层内神经元的存活率和连通性，减少了GABA能神经元的数量和水泡GABA转运蛋白（VGAT）的表达，诱发了神经炎症，并损害了淋巴间隙和空间记忆。或者，Slit2过表达会减弱功能障碍的神经元Ca2 +信号传导，可以防止梗死周围区域神经元死亡以及顶叶皮质连接性的丧失，增加GABA能的中间神经元数目和VGAT表达，减轻神经炎症，并改善淋巴管清除和空间记忆。我们的结果强烈表明，Slit2的过度表达可预防MIs功能障碍，而MIs是老年人认知障碍的潜在治疗靶标。