C-C motif chemokine 3 interferes with oligodendrocyte maturation in the brain

White matter alteration caused by abnormal myelination is a major contribution to the pathophysiology of autism spectrum disorder (ASD). We previously reported that mice prenatally exposed to valproic acid (VPA) showed increased expression of C-C motif chemokine ligand 3 (CCL3) in the developing hippocampus, and that antagonizing C-C chemokine receptor type 5 (CCR5), a CCL3 receptor, recovered neural circuit dysfunction. Therefore, we investigated the effects of CCL3 on oligodendrocyte differentiation. Treatment of the rat oligodendrocyte precursor cell (OPC) line CG4 and mouse primary OPC with CCL3 promoted CG4 migration. Conditioned media from BV-2 and primary microglia also promoted CG4 migration, and this promotion was cancelled by the CCR5 antagonist, maraviroc. CCL3 inhibited the differentiation of primary OPCs into mature oligodendrocytes. Therefore, microglia-derived CCL3 acts directly on OPCs by promoting their migration and inhibiting their differentiation. In organotypic whole-brain slice cultures, the expression of mature oligodendrocyte markers and the stained area of myelin basic protein (MBP) increased in a time-dependent manner. Treatment of slices with CCL3 reduced the expression of mature oligodendrocyte markers and the area of MBP staining. These changes were reversed by maraviroc pretreatment. In mice prenatally exposed to VPA, the expression of mature oligodendrocyte markers was reduced, myelin was thinner at 10 days of age, and axonal diameter was reduced at 8 weeks of age compared with control mice. These abnormalities were ameliorated by maraviroc treatment. Collectively, CCL3 interferes with oligodendrocyte maturation, thereby delaying axonal myelination and resulting in neural circuit dysfunction mediated by VPA.