Impaired cognitive function and altered hippocampal synaptic plasticity in mice lacking dermatan sulfotransferase Chst14/D4st1

Qifa Li, Xuefei Wu, Xueyan Na, Biying Ge, Qiong Wu, Xuewen Guo, Michael Ntim, Yue Zhang, Yiping Sun, Jinyi Yang, Zhicheng Xiao, Jie Zhao, Shao Li

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 (Chst14 −/− ) 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 Chst14 −/− 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 Chst14 −/− 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 Chst14 −/− 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.

Original languageEnglish
Article number26
Number of pages10
JournalFrontiers in Molecular Neuroscience
Volume12
DOIs
Publication statusPublished - 11 Feb 2019

Keywords

  • Chst14/D4st1
  • Dermatan sulfate
  • Learning and memory
  • LTP
  • Synaptic plasticity

Cite this

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. / Impaired cognitive function and altered hippocampal synaptic plasticity in mice lacking dermatan sulfotransferase Chst14/D4st1. In: Frontiers in Molecular Neuroscience. 2019 ; Vol. 12.
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title = "Impaired cognitive function and altered hippocampal synaptic plasticity in mice lacking dermatan sulfotransferase Chst14/D4st1",
abstract = "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 (Chst14 −/− ) 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 Chst14 −/− 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 Chst14 −/− 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 Chst14 −/− 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.",
keywords = "Chst14/D4st1, Dermatan sulfate, Learning and memory, LTP, Synaptic plasticity",
author = "Qifa Li and Xuefei Wu and Xueyan Na and Biying Ge and Qiong Wu and Xuewen Guo and Michael Ntim and Yue Zhang and Yiping Sun and Jinyi Yang and Zhicheng Xiao and Jie Zhao and Shao Li",
year = "2019",
month = "2",
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doi = "10.3389/fnmol.2019.00026",
language = "English",
volume = "12",
journal = "Frontiers in Molecular Neuroscience",
issn = "1662-5099",
publisher = "Frontiers Research Foundation",

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Impaired cognitive function and altered hippocampal synaptic plasticity in mice lacking dermatan sulfotransferase Chst14/D4st1. / 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.

In: Frontiers in Molecular Neuroscience, Vol. 12, 26, 11.02.2019.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Impaired cognitive function and altered hippocampal synaptic plasticity in mice lacking dermatan sulfotransferase Chst14/D4st1

AU - Li, Qifa

AU - Wu, Xuefei

AU - Na, Xueyan

AU - Ge, Biying

AU - Wu, Qiong

AU - Guo, Xuewen

AU - Ntim, Michael

AU - Zhang, Yue

AU - Sun, Yiping

AU - Yang, Jinyi

AU - Xiao, Zhicheng

AU - Zhao, Jie

AU - Li, Shao

PY - 2019/2/11

Y1 - 2019/2/11

N2 - 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 (Chst14 −/− ) 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 Chst14 −/− 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 Chst14 −/− 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 Chst14 −/− 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.

AB - 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 (Chst14 −/− ) 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 Chst14 −/− 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 Chst14 −/− 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 Chst14 −/− 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.

KW - Chst14/D4st1

KW - Dermatan sulfate

KW - Learning and memory

KW - LTP

KW - Synaptic plasticity

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U2 - 10.3389/fnmol.2019.00026

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