Oligodendrocyte and Astrocyte Dynamics During Short-Term Cuprizone Treatment.

PURPOSE: Glial cells, including oligodendrocytes (OLs), astrocytes, and microglia, are brain cells that support and dynamically interact with neurons and each other. These intercellular dynamics undergo changes during stress and disease states. Studies have reported cross talk between glial cells, such as astrocytes, microglia, and OL precursor cells (OPCs), and recruitment to central nervous system (CNS) lesions. However, the dynamics of this interaction are still unclear, especially during the early time point of exposure to cuprizone (CPZ).

METHODS

In this study, we exposed mice to CPZ treatment for a short duration (3 days and 1 week); we used immunohistochemistry to quantify Aspartoacylase (ASPA)-positive OLs, complement component 3d (C3d)-positive astrocytes (A1 subtype), and epithelial membrane protein 1  (Emp1)-positive astrocytes (A2 subtype). Gene expression levels of myelinating OLs were quantified using reverse transcription polymerase chain reaction (RT-PCR), and protein expression of C3d and Emp1 was quantified using Western blot.

FINDING: After 3 days of CPZ treatment, there was a significant increase in the expression of the astrocyte A2 marker (Emp1) and a significant decrease in mature OLs marked by ASPA. No significance was observed for C3d at 3 days and 1 week. Additionally, the Myelin Basic Protein (MBP) gene, which also shows the expression level of myelin, was significantly downregulated at 3 days. Previous work indicates that CPZ causes blood-brain barrier (BBB) permeability as early as 3 days, with subsequent microglial and astrocyte activation before demyelination.

CONCLUSION

This study suggests an interaction between OLs death and astrocyte subtypes activation during CPZ treatment at early time points (3 days and 1 week) before overt demyelination. Understanding this cross talk and the changes in their activation and interaction is important for developing methods to prevent or reverse demyelination.