The extracellular matrix (ECM) of the central nervous system (CNS) primarily consists of hyaluronan (HA) and chondroitin sulfate proteoglycans (CSPGs). HA polymer serves as the backbone of the ECM and binds multiple CSPGs, forming a macromolecular complex in the extracellular space. Recent advances in our understanding of the molecular mechanisms underlying the organization and remodeling of the ECM during the development, maturation, and aging of the CNS are reviewed herein. A juvenile-type ECM, which shows a relatively loose and diffuse structure, plays crucial roles in neural developmental processes, such as neurogenesis, neuronal migration, and neurite outgrowth. During late postnatal development, the juvenile-type ECM is replaced by an adult-type mature ECM, which drives the transition from more plastic, juvenile neural circuits to a more stable adult circuit. Perineuronal nets (PNNs), a prominent example of the adult-type ECM, are mesh-like insoluble aggregates that form around subpopulations of neurons and promote memory retention and consolidation in the adult brain. Furthermore, emerging evidence indicates that the degradation of ECM molecules during aging may contribute to an age-dependent decline in brain function.

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.

Multivalent ligands with a regular arrangement of carbohydrates, such as natural glycoproteins, glycopeptides, and branched oligosaccharides, play an important role as in vivo molecular recognition elements for lectins. In recent years, attempts have been actively made to develop functional glyco-materials, such as cell culture substrates and virus adsorbents, by artificially imitating and reproducing the molecular recognition ability of natural multivalent glycans. Multivalent lectins with two or more sugar-binding sites bind to multivalent ligands in a structure-specific manner and are thereby crosslinked to form an aggregate. Although this cross-linking reaction is a universal phenomenon, many unclear points remain in the series of mechanisms involved in the formation of cross-linked lectin complexes. Furthermore, multivalent lectins are also present on the surface of pathogenic bacteria and pathogenic viruses, and may be used as molecular targets in the development of toxin protein neutralizers and antiviral agents. To address these issues, middle-molecular-weight glycoclusters with a well-defined structure and a controlled number of sugar chain clusters have been designed and synthesized as potential cross-linking agents for multivalent lectins. This review provides an overview of the synthesis and utilization of middle-molecular-weight glycoclusters.

The extracellular matrix (ECM) of the central nervous system (CNS) primarily consists of hyaluronan (HA) and chondroitin sulfate proteoglycans (CSPGs). HA polymer serves as the backbone of the ECM and binds multiple CSPGs, forming a macromolecular complex in the extracellular space. Recent advances in our understanding of the molecular mechanisms underlying the organization and remodeling of the ECM during the development, maturation, and aging of the CNS are reviewed herein. A juvenile-type ECM, which shows a relatively loose and diffuse structure, plays crucial roles in neural developmental processes, such as neurogenesis, neuronal migration, and neurite outgrowth. During late postnatal development, the juvenile-type ECM is replaced by an adult-type mature ECM, which drives the transition from more plastic, juvenile neural circuits to a more stable adult circuit. Perineuronal nets (PNNs), a prominent example of the adult-type ECM, are mesh-like insoluble aggregates that form around subpopulations of neurons and promote memory retention and consolidation in the adult brain. Furthermore, emerging evidence indicates that the degradation of ECM molecules during aging may contribute to an age-dependent decline in brain function.

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.

Multivalent ligands with a regular arrangement of carbohydrates, such as natural glycoproteins, glycopeptides, and branched oligosaccharides, play an important role as in vivo molecular recognition elements for lectins. In recent years, attempts have been actively made to develop functional glyco-materials, such as cell culture substrates and virus adsorbents, by artificially imitating and reproducing the molecular recognition ability of natural multivalent glycans. Multivalent lectins with two or more sugar-binding sites bind to multivalent ligands in a structure-specific manner and are thereby crosslinked to form an aggregate. Although this cross-linking reaction is a universal phenomenon, many unclear points remain in the series of mechanisms involved in the formation of cross-linked lectin complexes. Furthermore, multivalent lectins are also present on the surface of pathogenic bacteria and pathogenic viruses, and may be used as molecular targets in the development of toxin protein neutralizers and antiviral agents. To address these issues, middle-molecular-weight glycoclusters with a well-defined structure and a controlled number of sugar chain clusters have been designed and synthesized as potential cross-linking agents for multivalent lectins. This review provides an overview of the synthesis and utilization of middle-molecular-weight glycoclusters.