Glucocorticoids target postnatal oligodendrocyte precursor cells to modulate adult hippocampal network plasticity and stress-induced behavior

Glucocorticoid receptors (GRs) are key mediators of how the stress hormone glucocorticoids (GCs) shape postnatal brain development and adaptive plasticity. Because GC signaling is critical during this period, postnatal GC concentrations are tightly regulated in the brain, whereas excessive levels of circulating GCs can disrupt developmental trajectories and increase the risk of psychiatric disorders later in life. GR function influences multiple neural cell types, but its cell-specific roles, particularly early in development, remain poorly understood. Oligodendrocyte precursor cells (OPCs), which generate myelinating oligodendrocytes and actively modulate neuronal networks, express GRs and can therefore respond to fluctuations in GC levels. Although excessive GC exposure during early life adversity has been linked to changes in OPC development, the physiological role of GR signaling specifically within OPCs remains unclear. To address this, we conditionally deleted GRs in postnatal OPCs in mice to investigate the role of physiological GC signaling in OPC proliferation and maturation, as well as in neuronal network activity and behavior. This deletion resulted in reduced oligodendrocyte and myelinated axon density in the hippocampus, sex-specific alterations in hippocampal activity and long-term potentiation following acute challenge, and impairments in memory formation in adulthood. Our findings reveal a novel, OPC-specific role for GRs and suggest that physiological GR activity in the oligodendrocyte lineage contributes to normal hippocampal plasticity, learning and memory. Significance Statement Glucocorticoid receptors (GRs) mediate the effects of the stress hormone glucocorticoids (GCs) on postnatal brain development and adaptive plasticity. While the function of GRs in neurons is well characterized, much less is known about their role in oligodendrocyte precursor cells (OPCs). OPCs, which give rise to myelinating oligodendrocytes and participate in the modulation of neuronal networks, express GRs and can therefore sense fluctuations in GCs during stress response; however, the physiological role of GRs in OPCs remains unclear. In this study, we found that deleting GRs in early postnatal OPCs reduced the density of oligodendrocytes and of myelinated axons, altered hippocampal activity and long-term potentiation in response to acute challenge, and impaired memory formation in adult mice. These findings identify OPCs as key targets of GR signaling and suggest that physiological receptor activity in the oligodendrocyte lineage contributes to normal hippocampal plasticity, learning, and memory. Competing Interest Statement The authors have declared no competing interest. Footnotes

and Discussion have been revised; Two new figures were added and two figures were revised; the author list updated; Supplemental files were updated.