Sarm1 deletion reduces axon damage, demyelination, and white matter atrophy after experimental traumatic brain injury

Traumatic brain injury (TBI) often damages axons in white matter tracts and causes corpus callosum (CC) atrophy in chronic TBI patients. Injured axons encounter irreversible damage if transected, or alternatively may maintain continuity and subsequently either recover or degenerate. Secondary mechanisms can cause further axon damage, myelin pathology, and neuroinflammation. Molecular mechanisms regulating the progression of white matter pathology indicate potential therapeutic targets. SARM1 is essential for execution of the conserved axon death pathway. We examined white matter pathology following mild TBI with CC traumatic axonal injury in mice with Sarml gene deletion (Sarm1 - / -). High resolution ultrastructural analysis at 3 days post-TBI revealed dramatically reduced axon damage in Sarm1 - / - mice, as compared to Sarm1 + / + wild-type controls. Sarml deletion produced larger axons with thinner myelin, and attenuated TBI induced demyelination, i.e. myelin loss along apparently intact axons. At 6 weeks post-TBI, Sarm1 - / - mice had less demyelination and thinner myelin than Sarm1 + / + mice, but axonal protection was no longer observed. We next used Thy1-YFP crosses to assess Sarml involvement in white matter neurodegeneration and neuroinflammation at 8 weeks post-TBI, when significant CC atrophy indicates chronic pathology. Thyl-YFP expression demonstrated continued CC axon damage yet absence of overt cortical pathology. Importantly, significant CC atrophy in Thy1-YFP/Sarm1 + / + mice was associated with reduced neurofilament immunolabeling of axons. Both effects were attenuated in Thy1-YFP/Sarm1 - / - mice. Surprisingly, Thy1-YFP/Sarm1 - / - mice had increased CC astrogliosis. This study demonstrates that Sarmi inactivation reduces demyelination, and white matter atrophy after TBI, while the post-injury stage impacts when axon protection is effective.