Focal white matter lesions drive inflammation, neuronal dysfunction and synapse loss in the grey matter

Focal white matter lesions occur in most neurodegenerative disorders1-4. They are well characterised in multiple sclerosis (MS) but much less understood in other conditions. Despite occurring early in disease, white matter lesions are considered either independent of or secondary to grey matter neuroinflammation, synaptic loss and altered neuronal activity5-8. Notably their functional impact on neuronal circuits has been overlooked. To address this, we performed a focal white matter lesion in an anatomically well-defined circuit, in which white matter lesions occur in many neurodegenerative disorders. Here we show that focal white matter lesions evoke transient neuronal activity changes and microgliosis, synaptic loss and increased engulfment in the grey matter, which resolves by the time myelin regeneration completes. Synaptic loss and microgliosis are often considered detrimental but we show they are instead an integral part of the myelin regenerative process. When we prevent these transient changes in the grey matter, myelin regeneration is blocked in the white matter. Conversely, inducing myelin regeneration failure leads to chronic neuroinflammation in the grey matter, suggesting that myelin regeneration failure drives sustained microglial activation. This recapitulates the low-grade inflammation considered to be a dominant mechanism underlying neurodegeneration8-11. Hence, we present a novel mechanism that may underlie multiple conditions and highlight the potential of targeting myelin regeneration to prevent chronic neuroinflammation. Overall design: To test for accompanying transcriptional changes in demyelinated neurons within the IO, we injected fast blue into the CCP along with EB and sorted and performed RNA-seq on labelled cells. We performed transcriptional profiling for 4 time points including Saline samples as a reference.