# 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.

## Key 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.