68 - The role of the Wallerian degeneration executor SARM1 in distal and proximal traumatic axonopathy and plasticity following traumatic brain injury.

Abstract Text: Traumatic axonal injury (TAI) and the associated traumatic axonopathy are very common pathologies in traumatic brain injury (TBI) and contribute to significant neurological morbidity. The murine visual system is ideal for the study of mechanisms and treatments for TAI due to its unique anatomical configuration allowing the separate study of perikarya, axons and terminal fields and its consistent degeneration in a variety of TBI models, including impact acceleration TBI (IA-TBI). We have previously established that the perikarya and proximal, but not distal portions of injured RGCs respond to the blockade of mixed lineage kinases DLK and LZK. . Here we explored the ultrastructural and other features of traumatic axonopathy in the optic nerve, the course of retinocollicular system plasticity, as well as the role of the Sterile alpha and TIR-motif containing 1 (SARM1), the key executor of Wallerian degeneration, in the progressive breakdown of distal and proximal segments of optic nerves following IA-TBI.
Wt and SARM1 KO mice received IA-TBI or sham injury and were allowed to survive for 3, 7, 14 and 21 days. Morphological features of TAI and traumatic axonopathy were assessed by electron microscopy while normal and pathological axon profiles were counted on semithin optic nerve sections using stereological methods. For the study of retinocollicular projections, retinas were transduced with an AAV vector for the genetic tracing of axons (cytosolic tdTomato) and synapses (SypGFP). Functional changes in visual pathway were recorded using scotopic electroretinogram and visual evoked potentials.
In both wt and SARM1 KO mice, IA-TBI results in TAI characterized by acute and variable degrees of axonal and myelin perturbations, axonal separation into proximal and distal segments and an evolving axonopathy and degeneration of the two segments. Timing and magnitude of pathology in the distal ON differ significantly based on genotype: Sarm1 deletion significantly reduces pathology by 30-40 % on 7, 14 and 21 days post-injury and also reduces axon loss by 50% on 7 and 14 days, effect that tapers at 21 days (20%, ns). The effects of Sarm1 deletion may extend to the protection of the retinocollicular terminal fields. In addition to morphological changes, there is also decrease in the amplitude of ERG a- and b- wave, and an increase in VEP N1 wave latency up to 7 days after IA-TBI, changes partially prevented by Sarm1 deletion. Despite such dramatic effects on the course of distal axonopathy and on measures of visual function, Sarm1 deletion does not prevent the long-term attrition of RGC cell bodies and proximal axons.
Our data are suggestive of the molecular differentiation of proximal and distal axonopathy associated with TAI, and the selective role of SARM1 signaling in distal axonopathic processes.

Keywords: Wallerian degeneration, axonopathy, white matter, myelin, microglia, electron microscopy, traumatic axonal injury, diffuse axonal injury, collateral sprouting, plasticity, Sarm1,