# Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination

## TL;DR

Removing microglia in the brain's cortex after demyelination boosts the number of oligodendrocytes, which could help treat multiple sclerosis.

## Contribution

This study reveals that transiently depleting reactive microglia in the cortex promotes oligodendrocyte regeneration after demyelination.

## Key findings

- Cortical microglia become reactive after demyelination and persist in this state during early recovery.
- Depleting microglia during recovery increases the density of mature/pre-myelinating oligodendrocytes.
- Reactive microglia in the deep cortex reduce oligodendrocyte density following demyelination.

## Abstract

Cortical demyelination is a critical contributor to progressive disease in multiple sclerosis (MS). The barriers to cortical remyelination following demyelination are not fully understood, and there are no remyelinating treatments for MS. We previously took advantage of the spatial and temporal resolution of longitudinal in vivo imaging to study cortical oligodendrocyte regeneration following cuprizone‐induced demyelination and found that oligodendrocyte regeneration was impaired. In this study, we investigated whether cortical reactive microglia disrupt oligodendrocyte regeneration. To do so, we used a combination of in situ RNA and immunofluorescence labeling to characterize cortical microglia reactive states following cuprizone‐mediated demyelination. We then depleted cortical microglia by administering a Csf1r inhibitor during the recovery period from cuprizone and quantified oligodendrocyte recovery. We found that following cortical demyelination, deep cortical microglia change morphology, downregulate homeostatic markers (P2RY12, TMEM119), and upregulate a marker (CD68) associated with activated macrophages. These reactive changes persisted through early recovery post‐cuprizone but resolved by late recovery. Depleting cortical microglia post‐cuprizone restored the baseline density of deep cortical ASPA+ oligodendrocytes at early and late recovery. There were also more deep cortical BCAS1+ differentiating oligodendrocytes at early recovery when microglia were depleted, suggesting that transient deep cortical reactive microglia impair oligodendrocyte differentiation following demyelinating injury. Together, we found that cortical microglia adopt spatially restricted reactive functions after demyelination and deep cortical reactive microglia transiently reduce differentiating oligodendrocytes. A potential therapeutic strategy for progressive MS could involve targeting transiently reactive microglia at the right time and place in cortical lesions to promote oligodendrocyte regeneration.

Cuprizone demyelination induces transient reactive states in deep cortical microglia (MG) through early recovery.Depleting MG in recovery increases the number of deep cortical mature/pre‐myelinating oligodendrocytes.Deep cortical reactive MG reduce oligodendrocyte density after demyelination.

Cuprizone demyelination induces transient reactive states in deep cortical microglia (MG) through early recovery.

Depleting MG in recovery increases the number of deep cortical mature/pre‐myelinating oligodendrocytes.

Deep cortical reactive MG reduce oligodendrocyte density after demyelination.