Terminal Schwann Cells are Integral for Neuromuscular Junction Function and Reinnervation
Eric Balta, BS, BA1, Albina Jablonka-Shariff, PhD1, Johnny Chuieng-Yi Lu, MD, MS1, Katherine Bernadette Santosa, MD, MS1 and Alison K. Snyder-Warwick, MD2, (1)Washington University School of Medicine, St. Louis, MO, (2)Washington University School of Medicine, Saint Louis, MO
Introduction: Peripheral nerve injuries account for 5% of all hospital trauma patients in North America (Noble et al. 1998). Reinnervation capabilities are usually limited to 12-18 months following injury. Terminal Schwann cells (tSCs), are supportive glial cells that reside at the neuromuscular junction (NMJ), contribute to NMJ maintenance, and are active during reinnervation. The requirement of tSCs for NMJ function and reinnervation in mammalian species, however, is not known. In this study, we utilized immune-mediated tSC ablation to assess the contributions of these cells to NMJ maintenance and recovery. This knowledge will hopefully improve our ability to treat peripheral nerve injuries
Methods: Adult S100-GFP mice underwent injection of the right extensor digitorum longus (EDL) with either GD3 anti-disialosyl antibodies (i.e. experimental group) or Lactated Ringer's (i.e. control group), followed by normal human serum as a complement source. For nerve injury studies, mice underwent right peroneal nerve transection with repair simultaneously or 1 week prior to tSC ablation. Muscle force testing was performed at post-ablation days (PAD) 3 or 14 (no nerve injury) or 3 or 6 weeks after ablation and nerve injury (post-injury ablation, PIA). The EDL was harvested and stained with aBTX-Alexa 647 (selective for Acetylcholine Receptors) in order to identify and assess the NMJ.
Results: Morphologic testing showed the numbers of tSCs were reduced after ablation compared to controls at all time points (p<0.05). Even without nerve injury, there was a significant decrease in EDL force to 38% of control in the PAD14 group with 1-hour GD3 incubation (p<0.003). There were no differences in the PAD3 group compared to control. After nerve injury, motor endplate fragmentation was increased in mice that underwent tSC ablation versus control (PIA 3 wks: 22% vs 2%, p<0.01; PIA 6 wks: 27% vs 7%, p<0.01). EDL force was reduced at 64% of control at PIA 3 wks (p<0.05) and 50% of control at PIA 6 wks (p<0.001).
Conclusion: These data suggest tSC ablation affects both NMJ morphology and muscle function. tSCs are required for efficient NMJ function and reinnervation after nerve transection and repair. tSCs are a possible therapeutic target in patients with peripheral nerve injuries.
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