GPR17+ Oligodendrocyte Lineage Cells Regulate the Critical Period of Brain Development Through Novel Chondroitin...

The extracellular matrix (ECM) of the brain undergoes dynamic remodeling during development and is crucial for neuronal plasticity. While chondroitin sulfates (CS) regulate oligodendrocyte differentiation and myelination, their relationship with oligodendrocyte precursors (OPCs) and synaptic plasticity remains unclear. This study investigated a novel CS-rich ECM structure, its origin, and its role in synaptic plasticity. Using immunohistochemistry, disaccharide analysis, and dendritic spine characterization in mice, we examined postnatal development and analyzed single-cell RNA (scRNA) sequencing data from the National Center for Biotechnology Information database. We identified patch-like structures labeled with the chondroitin sulfate 56 (CS56) antibody (CS clusters) distinct from Wisteria floribunda agglutinin-positive perineuronal nets. Oligodendrocyte lineage cells expressing G protein-coupled receptor 17 (GPR17) localized at CS cluster centers, emerging postnatally and peaking at day 14, preceded CS cluster formation. ScRNA sequencing of Gpr17+ cells revealed the expression of carbohydrate sulfotransferase 3 (Chst3) and uronyl 2-sulfotransferase (Ust), genes coding enzymes synthesizing type C and D CS disaccharides, the primary components of the CS56 antibody epitope. Disaccharide analysis revealed elevated levels of type D chondroitin sulfate at day 35. Notably, dendritic spines within the CS clusters were longer and larger than those outside these regions, suggesting enhanced synaptic connectivity. Our findings reveal a CS-rich structure in the brain ECM that is causally linked to GPR17+ oligodendrocyte lineage cells and closely related to neuronal circuit development. The morphological differences in dendritic spines within CS clusters and persistence of GPR17+ oligodendrocyte lineage cells beyond the postnatal period suggest additional functions that warrant further investigation.