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

Focal white matter lesions occur in most neurodegenerative disorders. Despite occurring early in disease, white matter lesions are considered either independent of, or secondary to, grey matter neuroinflammation, synapse loss and altered neuronal activity. Notably their functional impact on neuronal circuits has been understudied. To address this, we generated 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, 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 that it is 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 grey matter microglial activation. This recapitulates the low-grade inflammation considered to be a dominant mechanism underlying neurodegeneration. Our findings reveal a form of regenerative plasticity coupling white matter integrity to grey matter function - a novel mechanism of neuroplasticity that may underlie multiple neurodegenerative conditions - and highlights the potential of targeting myelin regeneration to prevent chronic inflammation. Overall design: The caudal cerebellar peduncle (CCP) of 9–12-week-old Sprague Dawley rats was bilaterally injected stereotaxically using a 10 µl Hamilton syringe. 4 µl of saline (controls) or ethidium bromide (0.01% in saline) were injected at a rate of 1 µl min-1 to induce a focal white matter demyelination. CCP coordinates were -7.3 mm (dorsal-ventral, DV); -2.3 mm (anterior-posterior, AP); ±2.6 mm (medium-lateral, ML) from lambda. Rats were culled at 7 and 14 dpl.