Focal white matter lesions drive grey matter inflammation and synapse loss

Focal white matter lesions occur in most neurodegenerative disorders. Despite ooccurring early in disease, white matter lesions are considered independent of, or secondary to, grey matter neuroinflammation, synapse loss and altered neuronal activity4–7. Notably, their functional impact on neuronal circuits remains understudied. To address this, we generated a focal white matter lesion in a clinically relevant, anatomically well-defined circuit, in which they occur in many neurodegenerative disorders8–10. Here we show that focal white matter lesions evoke transient neuronal activity changes and microgliosis, with subsequent synapse loss and increased microglia engulfment in the grey matter, which is reversed if myelin regeneration completes. Grey matter microgliosis is often considered detrimental but we show it is an integral part of regeneration. Preventing these transient changes in the grey matter blocks myelin regeneration in the white matter. Conversely, inducing myelin regeneration failure leads to chronic grey matter neuroinflammation. This recapitulates the low-grade inflammation considered to be a dominant mechanism underlying neurodegeneration7,11,12. Our findings reveal a form of regenerative plasticity coupling white matter integrity to grey matter function, which may underlie multiple neurodegenerative conditions, and highlight the potential of targeting myelin regeneration to prevent chronic neuroinflammation.