Glial D-serine modulates oligodendrocyte lineage progression under inflammatory conditions

TL;DR

This study shows that D-serine released by glial cells affects how oligodendrocytes mature during inflammation, potentially impairing myelin repair.

Contribution

The study reveals a novel role for glial D-serine in modulating oligodendrocyte lineage progression via NMDAR-dependent mechanisms during inflammation.

Findings

D-serine exposure reduces OLIG2+ and MBP+ cells during late oligodendrocyte differentiation.

Inflammatory activation increases D-serine levels and affects OPC maturation through NMDARs.

Blocking D-serine or NMDARs prevents the observed effects on oligodendrocyte lineage progression.

Abstract

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.

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