Glypicans and Heparan Sulfate in Synaptic Development, Neural Plasticity, and Neurological Disorders

Abstract

Heparan sulfate proteoglycans (HSPGs) are components of the cell surface and extracellular matrix, which bear long polysaccharides called heparan sulfate (HS) attached to the core proteins. HSPGs interact with a variety of ligand proteins through the HS chains, and mutations in HSPG-related genes influence many biological processes and cause various diseases. In particular, recent findings from vertebrate and invertebrate studies have raised the importance of glycosylphosphatidylinositol-anchored HSPGs, glypicans, as central players in the development and functions of synapses. Glypicans are important components of the synapse-organizing protein complexes and serve as ligands for leucine-rich repeat transmembrane neuronal proteins (LRRTMs), leukocyte common antigen-related (LAR) family receptor protein tyrosine phosphatases (RPTPs), and G-protein-coupled receptor 158 (GPR158), regulating synapse formation. Many of these interactions are mediated by the HS chains of glypicans. Neurexins (Nrxs) are also synthesized as HSPGs and bind to some ligands in common with glypicans through HS chains. Therefore, glypicans and Nrxs may act competitively at the synapses. Furthermore, glypicans regulate the postsynaptic expression levels of ionotropic glutamate receptors, controlling the electrophysiological properties and non-canonical BMP signaling of synapses. Dysfunctions of glypicans lead to failures in neuronal network formation, malfunction of synapses, and abnormal behaviors that are characteristic of neurodevelopmental disorders. Recent human genetics revealed that glypicans and HS are associated with autism spectrum disorder, neuroticism, and schizophrenia. In this review, we introduce the studies showing the roles of glypicans and HS in synapse formation, neural plasticity, and neurological disorders, especially focusing on the mouse and Drosophila as potential models for human diseases.

Expression of Heparan Sulfate Endosulfatases in the Adult Mouse Brain: Co-expression of Sulf1 and Dopamine D1/D2 Receptors

“…Given that Sulf1 and Sulf2 show distinct expression patterns in the adult brain, it is possible that they have separate roles in different neural circuits dependent on their expressing regions. HSPGs act as synapse organizers and are implicated in synapse formation and neural plasticity ( Holt and Dickson, 2005 ; Condomitti and de Wit, 2018 ; Kamimura and Maeda, 2021 ). More specifically, in the drosophila neuromuscular junction, RNAi-mediated knockdown of heparan sulfate 6- O -sulfotransferase ( Hs6st ) and Sulf1 resulted in decrease and increase in the amplitude of the synaptic current, respectively ( Dani et al, 2012 ; Kamimura and Maeda, 2021 ), indicating regulatory roles of HS 6- O -sulfation in synaptic function.…”

“…Heparan sulfate proteoglycans (HSPGs) are glycoproteins present on the cell surface and in the extracellular matrix (ECM) of all animal cells. In the nervous system, they play critical roles in neuron growth, differentiation, migration, axon guidance, synapse formation, and synaptic plasticity ( Holt and Dickson, 2005 ; Condomitti and de Wit, 2018 ; Kamimura and Maeda, 2021 ). HSPGs are composed of a core protein and covalently attached heparan sulfate (HS) chains.…”

“…Although the roles of Sulfs in development have been extensively studied, their significance in adult brain functions remains largely unknown. Given that HSPGs are key components of synapse-organizing protein complexes and the well-known presynaptic organizers Neurexins are synthesized as HSPGs, it is possible that Sulfs are involved in synapse assembly, maturation, and plasticity through HS modification ( Condomitti and de Wit, 2018 ; Zhang et al, 2018 ; Kamimura and Maeda, 2021 ). Previously, we reported that in the adult rat brain, Sulf1 mRNA is expressed in the cerebral cortex, olfactory tubercle, hypothalamus, and choroid plexus ( Ohto et al, 2002 ), and Sulf2 mRNA, in the cerebral cortex, hippocampus CA3 region, and medial habenula ( Nagamine et al, 2005 ).…”

Neural Tissue Homeostasis and Repair Is Regulated via CS and DS Proteoglycan Motifs

“…This chapter highlights the roles of chondroitin sulfate (CS) and dermatan sulfate (DS)-proteoglycans (PGs) in neural biology, heparan sulfate (HS)-PGs were outside the scope of this review and thus are only briefly touched on. However many excellent reviews exist on HS-PGs and their interactions with extracellular matrix (ECM) components in neural development, neural function and potential in neural repair biology ( Condomitti and de Wit, 2018 ; Zhang P. et al, 2018 ; Roppongi et al, 2020 ; Xiong et al, 2020 ; Kamimura and Maeda, 2021 ; Sakamoto et al, 2021 ). Roles for HS-PGs in model developmental organisms such as Drosophila melanogaster and Caenorhabditis elegans have also been reviewed ( Díaz-Balzac et al, 2014 ; Blanchette et al, 2017 ; Kamimura and Maeda, 2017 ; Saied-Santiago et al, 2017 ) and the interested reader is referred to these excellent publications for further information.…”

“…With the identification of the multiple molecular determinants that provide neuronal connectivity, and with new insights into the modulatory extracellular information regulating axon guidance, neural network and synapse formation, a better understanding of the complexity that neurons face in a living organism is beginning to emerge. Attention is now returning to an ancient regulator of cell-cell interaction: the ECM ( Dityatev and Schachner, 2006 ; Dityatev et al, 2010 ; Miyata and Kitagawa, 2017 ; Nicholson and Hrabětová, 2017 ; Ferrer-Ferrer and Dityatev, 2018 ; Quraishe et al, 2018 ; Cope and Gould, 2019 ; Long and Huttner, 2019 ; Chelyshev et al, 2020 ; Jain et al, 2020 ; Wilson et al, 2020 ; Carulli and Verhaagen, 2021 ; Kamimura and Maeda, 2021 ; Shabani et al, 2021 ; Su et al, 2021 ). Among the many matrix components that influence neuronal connectivity, recent studies on the CS-PGs and HS-PGs indicate these ancient molecules form dynamic scaffolds that not only provide a protective environment around cells but are also a source of directive cues that modulate neuronal behavior and synaptic plasticity in tissue development ( Haylock-Jacobs et al, 2011 ; Hayes and Melrose, 2018 ; Hayes et al, 2018 ; Karamanos et al, 2018 ; Hayes and Melrose, 2020a ; Shabani et al, 2021 ).…”