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.

Cell-extrinsic requirement for sulfate in regulating hippocampal neurogenesis

“…Importantly, the sulfonation patterns of stem cell niche extracellular matrix proteoglycans can influence neurogenesis by regulating growth factor signalling; the most well-known being the regulation of fibroblast growth factor signalling by heparan sulfate proteoglycans within the V-SVZ (Mercier, 2016;Purushothaman et al, 2012;Yamada et al, 2017;Yu et al, 2017). Within the SGZ, chondroitin sulfate and dermatan sulfate also appear to play roles in regulating neurogenesis as well (Li et al, 2019;Yamada et al, 2018). It is possible that impaired sulfate availability during the critical postnatal developmental window, when the demand for sulfate is high, alters the patterning of ECM proteoglycans laid down in the neural stem cell niches.…”

Proteoglycans as Therapeutic Targets in Brain Cancer

“…Accordingly, Kijima et al studied surface marks from patient derived xenografts and cell lines based on array comparative genomic hybridization to investigate the early stages of GBM tumorigenesis ( 48 ). In additional to research that found raised levels of systemic inflammatory markers to be correlated with cardiovascular disease ( 49 ), a recent study revealed that the specific sulfation level of DS is crucial in synaptic plasticity and is related to changes in the expression of glutamate receptors and other associated synaptic proteins ( 50 ). As such, endocan became a valuable target for GBM diagnosis and therapy.…”

Backcrossing to an appropriate genetic background improves the birth rate of carbohydrate sulfotransferase 14 gene-deleted mice

“…Pathophysiological mechanisms and therapies are not yet established for the disease. Several reports show that Chst14 gene deletion induces changes in the spinal cord and nervous system functions [ 1 , 8 , 13 ] as well as an abnormality of blood capillaries in the placenta [ 18 ] of mice. However, a model animal that focuses on the skin and bone (tissues related to serious symptoms of mcEDS- CHST14 ) has not been reported.…”