Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination

Area of Science:

• Neuroscience
• Immunology
• Demyelinating Diseases

Background:

• Cortical demyelination contributes to progressive multiple sclerosis (MS).
• Understanding barriers to remyelination is crucial for developing MS treatments.
• Previous studies showed impaired oligodendrocyte regeneration in the cortex.

Purpose of the Study:

• To investigate if reactive microglia disrupt oligodendrocyte regeneration after cortical demyelination.
• To characterize the reactive states of cortical microglia.
• To determine the effect of microglia depletion on oligodendrocyte recovery.

Main Methods:

• Used cuprizone model for demyelination.
• Employed in situ RNA and immunofluorescence labeling to study microglia.
• Administered a Csf1r inhibitor to deplete cortical microglia during recovery.
• Quantified oligodendrocyte recovery using markers like ASPA and BCAS1.

Main Results:

• Cortical microglia exhibited reactive states, changing morphology and marker expression (e.g., CD68 upregulation).
• These reactive changes persisted into early recovery.
• Depleting microglia restored oligodendrocyte density and increased differentiating oligodendrocytes.
• Transient reactive microglia in deep cortex were found to impair oligodendrocyte differentiation.

Conclusions:

• Cortical microglia adopt spatially restricted reactive functions post-demyelination.
• Deep cortical reactive microglia transiently inhibit oligodendrocyte differentiation.
• Targeting these specific reactive microglia could be a therapeutic strategy for progressive MS.