Glial D-serine modulates oligodendrocyte lineage progression under inflammatory conditions

Inflammatory environments may shape oligodendrocyte lineage dynamics beyond classical cytokine signaling, in part through the release of glial neuromodulators. Here, we investigated whether inflammation-associated D-serine signaling modulates oligodendrocyte lineage progression. Using highly purified primary oligodendrocyte precursor cell (OPC) cultures, we show that D-serine exposure during late differentiation reduces the proportion of OLIG2⁺ and myelin basic protein-positive (MBP⁺) cells without altering net cell number, while selectively decreasing apoptosis within the mature MBP⁺ population. These findings indicate that D-serine attenuates late-stage lineage progression while preserving oligodendrocyte survival in vitro. In parallel, inflammatory activation of mixed glial cultures with lipopolysaccharide (LPS) increased tumor necrosis factor-α release, upregulated serine racemase expression, and elevated extracellular D-serine levels. Conditioned media from reactive glial cultures recapitulated the effects of D-serine on OPC maturation, which were prevented by enzymatic degradation of D-serine or pharmacological blockade of N-methyl-D-aspartate receptors (NMDARs). Together, these findings support the involvement of glia-derived D-serine as a modulatory signal influencing oligodendrocyte lineage progression consistent with NMDAR-dependent mechanisms under inflammatory conditions that may contribute to impaired remyelination.