Li Qifa, Wu Xuefei, Na Xueyan, Ge Biying, Wu Qiong, Guo Xuewen, Ntim Michael, Zhang Yue, Sun Yiping, Yang Jinyi, Xiao Zhicheng, Zhao Jie, Li Shao
Liaoning Provincial Key Laboratory of Cerebral Diseases, Department of Physiology, Dalian Medical University, Dalian, China.
National-Local Joint Engineering Research Center for Drug-Research and Development (R & D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, China.
Front Mol Neurosci. 2019 Feb 11;12:26. doi: 10.3389/fnmol.2019.00026. eCollection 2019.
Chondroitin sulfate (CS) and dermatan sulfate (DS) proteoglycans (PGs) are major extracellular matrix (ECM) components of the central nervous system (CNS). A large body of evidence has shown that CSPGs/DSPGs play critical roles in neuronal growth, axon guidance, and plasticity in the developing and mature CNS. It has been proposed that these PGs exert their function through specific interaction of CS/DS chains with its binding partners in a manner that depends on the sulfation patterns of CS/DS. It has been reported that dermatan 4-O-sulfotransferase-1 (Chst14/D4st1) specific for DS, but not chondroitin 4-O-sulfotransferase-1 (Chst11/C4st1) specific for CS, regulates proliferation and neurogenesis of neural stem cells (NSCs), indicating that CS and DS play distinct roles in the self-renewal and differentiation of NSCs. However, it remains unknown whether specific sulfation profiles of DS has any effect on CNS plasticity. In the present study, Chst14/D4st1-deficient ( ) mice was employed to investigate the involvement of DS in synaptic plasticity. First, behavior study using Morris Water Maze (MWM) showed that the spatial learning and memory of mice was impaired when compared to their wild type (WT) littermates. Corroborating the behavior result, long-term potentiation (LTP) at the hippocampal CA3-CA1 connection was reduced in mice compared to the WT mice. Finally, the protein levels of N-Methyl-D-aspartate (NMDA) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, postsynaptic density 95 (PSD95), growth associated protein 43 (GAP-43), synaptophysin (SYN) and N-ethylmaleimide sensitive factor (NSF) which are important in synaptic plasticity were examined and Chst14/D4st1 deficiency was shown to significantly reduce the expression of these proteins in the hippocampus. Further studies revealed that Akt/mammalian target rapamycin (mTOR) pathway proteins, including protein kinase B (p-Akt), p-mTOR and p-S6, were significantly lower in mice, which might contribute to the decreased protein expression. Together, this study reveals that specific sulfation of DS is critical in synaptic plasticity of the hippocampus and learning and memory, which might be associated with the changes in the expression of glutamate receptors and other synaptic proteins though Akt/mTOR pathway.
硫酸软骨素（CS）和硫酸皮肤素（DS）蛋白聚糖（PGs）是中枢神经系统（CNS）主要的细胞外基质（ECM）成分。大量证据表明，CSPGs/DSPGs在发育中和成熟的中枢神经系统的神经元生长、轴突导向和可塑性方面发挥着关键作用。有人提出，这些PGs通过CS/DS链与其结合伙伴的特异性相互作用发挥功能，这种相互作用方式取决于CS/DS的硫酸化模式。据报道，对DS具有特异性的硫酸皮肤素4-O-磺基转移酶-1（Chst14/D4st1），而非对CS具有特异性的硫酸软骨素4-O-磺基转移酶-1（Chst11/C4st1），调节神经干细胞（NSCs）的增殖和神经发生，这表明CS和DS在NSCs的自我更新和分化中发挥着不同的作用。然而，DS的特定硫酸化谱是否对中枢神经系统可塑性有任何影响仍不清楚。在本研究中，使用Chst14/D4st1基因敲除小鼠来研究DS在突触可塑性中的作用。首先，使用莫里斯水迷宫（MWM）进行的行为学研究表明，与野生型（WT）同窝小鼠相比，基因敲除小鼠的空间学习和记忆受损。与行为学结果一致，与WT小鼠相比，基因敲除小鼠海马CA3-CA1连接处的长时程增强（LTP）降低。最后，检测了在突触可塑性中起重要作用的N-甲基-D-天冬氨酸（NMDA）受体、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体（译者注：原文此处多了个括号，疑有误，已按正常内容翻译）、突触后致密蛋白95（PSD95）、生长相关蛋白43（GAP-43）、突触素（SYN）和N-乙基马来酰亚胺敏感因子（NSF）的蛋白水平，结果显示Chst14/D4st1基因敲除显著降低了海马中这些蛋白的表达。进一步研究表明，Akt/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路蛋白，包括蛋白激酶B（p-Akt）、p-mTOR和p-S6，在基因敲除小鼠中显著降低，这可能导致蛋白表达下降。总之，本研究揭示了DS的特定硫酸化在海马的突触可塑性以及学习和记忆中至关重要，这可能与谷氨酸受体和其他突触蛋白表达的变化通过Akt/mTOR信号通路有关。
