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.

Keywords: autism spectrum disorder; glypican; heparan sulfate proteoglycan; neurexin; schizophrenia; synapse-organizing protein; synaptic plasticity.

FIGURE 1

Vertebrate and Drosophila heparan sulfate proteoglycans (HSPGs) in the synapses. (A) Heparan sulfate (HS) chains of Nrx and GPC4 interact with multiple synapse-organizing proteins. Presynaptic Nrx interacts with Nlgn, LRRTM2, LRRTM4, and PTPσ. Presynaptic GPC4 interacts with LRRTM4, PTPσ, and GPR158. Nrx–PTPσ–LRRTM4 and GPC4–PTPσ–LRRTM4 complexes reside separately at the synapses. GPC4 is secreted from astrocytes and interacts with presynaptic PTPδ. (B) Functions of Drosophila HSPGs (Dnrx, Dlp, and Sdc) in the NMJ synapses. Dnrx interacts with Dnlgn through HS chains (Zhang et al., 2018). Sdc promotes Dlar signaling, whereas Dlp suppresses it. Anterograde Wg and retrograde Gbb activities are regulated by fine structures of HS chains, presumably of Sdc and/or Dlp. Dlp regulates non-canonical BMP signaling through GluRIIA. Nrx, neurexin; Nlgn, neuroligin; LRRTM, leucine-rich repeat transmembrane neuronal protein; GPC, glypican; PTP, protein tyrosine phosphatase; GPR, G protein-coupled receptor; Dnrx, Drosophila neurexin; Dnlgn, Drosophila neuroligin; DFz2, Drosophila Frizzled 2; BMPR, BMP (bone morphogenetic protein) receptor; Sdc, syndecan; Dlp, Dally-like protein; Wg, Wingless; Gbb, Glass bottom boat.

FIGURE 2

Dlp regulates synaptic plasticity at the Drosophila neuromuscular junction (NMJ). (A) The body wall muscles of Drosophila larva are innervated by type I glutamatergic motor neurons, which form synaptic boutons at the NMJs. Most larval body wall muscles are also innervated by octopaminergic type II neurons. (B) When larvae are placed under food deprivation conditions, octopamine is released from the type II boutons, and type II arbors rapidly extend new branches called synaptopods through the activation of Octβ2R octopamine autoreceptors. The acute acceleration of octopamine signaling by the growth of type II boutons leads to the rapid growth of type I boutons, which also express Octβ2R, and the increase of larval locomotor speed. (C) The expression of Dlp, which is a homolog of mammalian GPC4 and GPC6, is downregulated by octopamine signaling. Dlp suppresses the non-canonical BMP pathway that is composed of BMP receptor Wit and GluRIIA-containing iGluRs. Starvation-induced octopamine signaling downregulates Dlp expression, which leads to the activation of the non-canonical BMP signaling.

FIGURE 3

Hypothetical models for the regulation of synapse-organizing proteins by glypicans. (A) Fine structures of HS generated during biosynthetic processes may regulate the affinity strength between the synapse-organizing proteins affecting their signal strengths. (B) Extracellular regulation of HS structures by heparanase and 6-O endosulfatase (Sulf). Fragmentation of HS by heparanase and 6-O desulfation by Sulf may turn the signal off and change the signal strength of synapse-organizing proteins, respectively. (C) Effects of the glypican shedding on the synapse-organizing proteins. Shed glypicans may not activate synapse-organizing proteins (α pathway), but instead activate an alternative signaling pathway (β pathway).