ATF3 expression in L4 dorsal root ganglion neurons after L5 spinal nerve transection

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Abstract
Activating transcription factor 3 (ATF3) is a widely used marker of damaged primary sensory neurons that is induced in essentially all dorsal root ganglion (DRG) neurons by spinal nerve axotomy. Whether such injuries induce its expression in neurons of adjacent DRGs remains unknown. Following L5 spinal nerve ligation, experimental but not sham-operated rats develop thermal and mechanical hypersensitivity. In the L4 DRG, 11-12% of neurons were ATF3 positive by 1 day post-surgery, and numbers remain unchanged at 2 weeks. Importantly, sham exposure of the L5 spinal nerve produced a nearly identical number of ATF3-positive neurons in the L4 DRG and also a substantial increase in the L5 DRG, with a similar time-course to experimental animals. There was no correlation between behaviour and magnitude of ATF3 expression. Co-localization studies with the DRG injury markers galanin, neuropeptide Y and nitric oxide synthase (NOS) showed that approximately 75, 50 and 25%, respectively, of L4 ATF3-positive neurons co-expressed these markers after L5 transection or sham surgery. Additionally, increases in galanin and NOS were seen in ATF3-negative neurons in L4. Our results strongly suggest that the surgical exposure of spinal nerves induces ATF3 in the L4-5 DRG, irrespective of whether the L5 nerve is subsequently cut. This probably reflects minor damage to the neurons or their axons but nevertheless is sufficient to induce phenotypic plasticity. Caution is therefore warranted when interpreting the phenotypic plasticity of DRG neurons in adjacent ganglia in the absence of positive evidence that they are not damaged.