Astrocyte derived TSP2 contributes to synaptic alteration and visual dysfunction in retinal ischemia/reperfusion injury.
Astrocyte derived TSP2 contributes to synaptic alteration and visual dysfunction in retinal ischemia/reperfusion injury.
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星形胶质细胞衍生的 TSP2 有助于视网膜缺血/再灌注损伤中的突触改变和视觉功能障碍
DOI：
10.1186/s13578-022-00932-1
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发表时间：
2022-12-05
影响因子：
7.5
通讯作者：
Chen, Dan
中科院分区：
文献类型：
--
作者：
Hu, Tu;Meng, Shuhan;Zhang, Qianyue;Song, Shuang;Tan, Cheng;Huang, Jufang;Chen, Dan
关键词：
背景尽管目前的干预措施/疗法能够改善视网膜损伤/疾病后的神经元死亡，但视觉功能的恢复仍然不令人满意。以往的研究发现，视网膜病变后早期视网膜突触和神经突发生改变，这被认为不利于视觉信号的传递。然而，具体的配置文件和视网膜神经突和突触改变视网膜pathologies后的机制仍然知之甚少。MethodsHere，我们揭示了神经突和突触改变视网膜pathologies后的时空模式，使用大鼠模型的急性RI/R诱导高眼压（HIOP）与蛋白质印迹，免疫荧光，电子显微镜。我们通过病毒转导和药物注射进一步探讨了活化的星形胶质细胞及其衍生的血小板反应蛋白2（TSP 2）在RI/R诱导的视网膜神经突起和突触改变以及视觉功能障碍中的潜在作用。（突触素和突触素1）以及内网状层（IPL）中双极细胞和神经节细胞之间的突触囊泡，视功能的退化先于视网膜神经元的死亡。这些事件伴随着星形胶质细胞的激活。此外，我们发现，抑制星形胶质细胞的活化，（玻璃体内注射氟柠檬酸，FC），TSP 2敲低（TSP 2 shRNA-AAV转导），并竞争性抑制TSP 2和α2δ1的结合，（腹膜内注射加巴喷丁，结论（1）在RI/R损伤早期，GBP能有效地减轻RI/R损伤后视网膜神经元的损伤，大鼠视网膜发生神经节细胞轴突的变性以及在IPL中双极细胞和神经节细胞之间产生的补偿性突触重塑。这些变化发生早于神经节细胞层（GCL）中神经元的大量损失。(2)活化的星形胶质细胞分泌的TSP 2与α2δ1结合，介导了大鼠视网膜神经节细胞轴突的变性、强脉冲光下代偿性突触重构和RI/R损伤后的视觉功能障碍。
BackgroundDespite current intervention measures/therapies are able to ameliorate neuronal death following retinal injuries/diseases, the recovery of visual function remains unsatisfactory. Previous studies revealed that the retinal synapse and neurite changed during the early stage after retinopathy, which was considered to be detrimental to visual signal transmission. However, the specific profiles and the mechanisms underlying retinal neurite and synaptic alteration after retinal pathologies remain poorly understood.MethodsHere, we revealed the spatiotemporal pattern of neurite and synaptic alteration following retinal pathologies using a rat model of acute RI/R induced by high intraocular pressure (HIOP) with Western blotting, Immunofluorescence, and electron microscopy. We further explored the potential role of activated astrocytes and their derived thrombospondin 2 (TSP2) in RI/R induced retinal neurite and synaptic alteration and visual dysfunction through viral transduction and drug injection.ResultsWe found a defasciculation of RGC axons, a compensatory increase of presynaptic proteins (synaptophysin and synapsin 1) and synaptic vesicles between bipolar cells and ganglion cells in the inner plexiform layer (IPL), and the degenerated visual function preceded the neuronal death in rat retinae. These events were accompanied by the activation of astrocytes. Furthermore, we showed that suppressing the activation of astrocytes (intravitreal injection of fluorocitric acid, FC), TSP2 knockdown (TSP2 shRNA-AAV transduction), and competitively inhibiting the binding of TSP2 and α2δ1 (intraperitoneal injection of gabapentin, GBP) effectively alleviated the retinal synaptic and neurite alteration and the visual dysfunction following RI/R injury.Conclusions(1) At the early stage following RI/R injury, the rat retinae develop a degeneration of ganglion cell axons and the resulting compensatory synaptic remodeling between bipolar cells and ganglion cells in IPL. These changes occur earlier than the massive loss of neurons in the ganglion cell layer (GCL). (2) Activated astrocytes may secret TSP2, which bind to α2δ1, to mediate the degeneration of rat retinal ganglion cell axons, compensatory synaptic remodeling in IPL, and visual dysfunction following RI/R injury.
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大鼠视网膜中受体相互作用蛋白3的差异神经元表达：参与缺血应激反应
影响因子：
2.4
作者：
Huang JF;Shang L;Zhang MQ;Wang H;Chen D;Tong JB;Huang H;Yan XX;Zeng LP;Xiong K
通讯作者：
Xiong K
影响因子：
4.8
作者：
Gee, NS;Brown, JP;Woodruff, GN
通讯作者：
Woodruff, GN
影响因子：
5.6
作者：
Arteaga O;Álvarez A;Revuelta M;Santaolalla F;Urtasun A;Hilario E
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Hilario E
影响因子：
16.2
作者：
Kuo SP;Schwartz GW;Rieke F
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Rieke F
视网膜神经节细胞变性是拓扑的，但在DBA/2J小鼠中不是特异性细胞类型。
影响因子：
7.8
作者：
Jakobs, Tatjana C;Libby, Richard T;Ben, Yixin;John, Simon W M;Masland, Richard H
通讯作者：
Masland, Richard H