Keisuke Kamimura

Heparan sulfate proteoglycans (HSPGs) interact with various proteins through the HS chains and regulate many biological processes, and mutations in HSPG genes cause a variety of diseases. Recent studies in vertebrates and invertebrates have highlighted the importance of HSPGs glypicans in the development and function of synapses. Glypicans interact with various synapse-organizing proteins, such as LRRTMs and LAR family RPTPs, regulating synapse formation. Well-known presynaptic organizers, neurexins, function as HSPGs and bind to several proteins in common with glypicans through HS chains. Furthermore, glypicans regulate the postsynaptic levels of ionotropic glutamate receptors, controlling synaptic transmission. Mutations in glypican genes in model organisms affect synaptic development and function and cause abnormal behaviors. Recent human genetic studies also revealed associations of glypicans and HS with autism spectrum disorder. In this minireview, I describe the roles of glypicans and HS in synapse formation and neural plasticity as well as involvement in neurological diseases.

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 andDrosophilaas potential models for human diseases.