Loss of Sarm1 Mitigates Axonal Degeneration and Promotes Neuronal Regeneration After Ischemic Stroke

Axonal degeneration is a core feature of ischemic brain injury that limits functional recovery. The pro-degenerative molecule Sarm1 is required for Wallerian axon degeneration after traumatic and chemotoxic nerve injuries, however it is unclear if a similar mechanism mediates axonal degradation after ischemic injury. Here we show that loss of Sarm1 in male mice tested results in profound attenuation of axonal degeneration after focal ischemia to the subcortical white matter. Moreover, absence of Sarm1 significantly promotes the survival of neurons distal but connected to the infarct after ischemic injuries to the subcortical white matter as well as to the cortex. To further understand the mechanism of Sarm1-/- mediated neuronal protection, we performed differential gene expression analysis of male wildtype and Sarm1-/- stroke-injured neurons and found that that loss of Sarm1 activates a pro-regenerative molecular program that promotes new axon and synapse formation after white matter ischemia. Using a functional genomics approach to recapitulate such a molecular program in Sarm1-/- neurons, we identify molecular compounds sufficient to enhance cortical neurite outgrowth in vitro, and all of which elicit a conserved epigenetic signature promoting axonogenesis. These results indicate that Sarm1 concurrently promotes axonal degeneration and inhibits a regenerative program encoded at the level of the epigenome that can be modulated pharmacologically. Our findings thus reveal a novel role for Sarm1 as a crucial regulator of both axonal degeneration and axonal remodeling after ischemic stroke. Male C57BL/6 control mice and Sarm1 -/- mice were used at 3-6 months of age. Stroke was induced by focal injection of Lnio in subcortical white matter. 7 days after stroke induction, neurons were sorted via negative selection of CD11b and positive selection of NCAM using magnetic beads. RNA was isolated from the neurons and normalized using cell counts. This RNA was used for differential gene expression analysis between Sarm1 -/- neurons and wild-type neurons under stroke injury conditions.