Journal of Molecular Neuroscience

, Volume 67, Issue 4, pp 589–594 | Cite as

The Effect of Neuronal Activity on Glial Thrombin Generation

  • Orna GeraEmail author
  • Efrat Shavit-Stein
  • Joab Chapman


Thrombin through its receptor PAR-1 plays an important role in the peripheral nervous system. PAR-1 is located at the microvilli of Schwann cells at the node of Ranvier, and thrombin is generated by the coagulation system on these glial structures. In the present study, we examined the link between neuronal activity and modulation of thrombin generation by glial Schwann cells. Thrombin activity was assessed in sciatic nerves in reaction to high KCl as a model of neuronal activity. We demonstrated a significant transient effect of high KCL on thrombin activity (F(5, 20) = 42.65, p < 0.0001, by ANOVA) compared to normal KCl levels. Since the sciatic nerve includes components of axons and Schwann cell myelin sheath, we continued to investigate the effect of high KCl on a Schwannoma cell line as a model for nodal Schwann cell microvilli. We demonstrated a transient decrease in thrombin activity in response to high extracellular KCl (F(1, 18) = 9.56, p = 0.0063). The major neuronal inhibitor of thrombin is PN-1, and we therefore measured the effect of high KCL on PN-1 immunofluorescence intensity. We found significantly higher PN-1 staining intensity 3 min after the application of high KCL in comparison to cells exposed to high KCL for 7 min and to cells in regular KCL (F(2, 102) = 8.4737, p < 0.0004), and this effect may explain the changes in thrombin activity. The present results support an interaction between neuronal activity and the coagulation pathway as a novel mechanism for neuron-glia crosstalk at the node of Ranvier.


Thrombin High KCl Sciatic nerve Schwannoma 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.


  1. Barik A, Li L, Sathyamurthy A, Xiong W-C, Mei L (2016) Schwann cells in neuromuscular junction formation and maintenance. J Neurosci 36(38):9770–9781 Available from: CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bushi D, Gera O, Kostenich G, Shavit-Stein E, Weiss R, Chapman J, Tanne D (2016) A novel histochemical method for the visualization of thrombin activity in the nervous system. Neuroscience 320:93–104CrossRefPubMedGoogle Scholar
  3. Chiu SY (1991) Functions and distribution of voltage-gated sodium and potassium channels in mammalian Schwann-cells. Glia 4(6):541–558 Available from: isi: A1991GK70100001CrossRefPubMedGoogle Scholar
  4. Festoff BW, Ameenuddin S, Santacruz K, Morser J, Suo Z, Arnold PM et al (2004) Neuroprotective effects of recombinant thrombomodulin in controlled contusion spinal cord injury implicates thrombin signaling. J Neurotrauma 21(7):907–922 Available from: CrossRefPubMedGoogle Scholar
  5. Gera O, Shavit-Stein E, Bushi D, Harnof S, Shimon MB, Weiss R, Golderman V, Dori A, Maggio N, Finegold K, Chapman J (2016) Thrombin and protein C pathway in peripheral nerve Schwann cells. Neuroscience 339:587–598CrossRefPubMedGoogle Scholar
  6. Gera O, Bushi D, Ben Shimon M, Artan-Furman A, Harnof S, Maggio N, Dori A, Chapman J, Shavit-Stein E (2018) Local regulation of thrombin activity by Factor Xa in peripheral nerve Schwann cells. Neuroscience 371:445–454CrossRefPubMedGoogle Scholar
  7. Gray PTA, Bevan S, Ritchie JM (1984) High conductance anion-selective channels in rat cultured Schwann cells. Proc R Soc Lond Biol Sci 221(1225):395–409CrossRefGoogle Scholar
  8. Haydon PG, Carmignoto G (2006) Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev 86:1009–1031CrossRefPubMedGoogle Scholar
  9. Jha MK, Seo M, Kim JH, Kim BG, Cho JY, Suk K (2013) The secretome signature of reactive glial cells and its pathological implications. Biochim Biophys Acta Proteins Proteomics 1834(11):2418–2428. CrossRefGoogle Scholar
  10. Maggio N, Itsekson Z, Dominissini D, Blatt I, Amariglio N, Rechavi G et al (2013) Thrombin regulation of synaptic plasticity: implications for physiology and pathology. Exp Neurol 247:595–604. CrossRefPubMedGoogle Scholar
  11. Poliak S, Peles E (2003) The local differentiation of myelinated axons at nodes of ranvier. Nat Rev Neurosci 4(12):968–980CrossRefPubMedGoogle Scholar
  12. Rosenblatt DE, Cotman CW, Nieto-Sampedro M, Rowe JW, Knauer DJ (1987) Identification of a protease inhibitor produced by astrocytes that is structurally and functionally homologous to human protease nexin-I. Brain Res 415(1):40–48CrossRefPubMedGoogle Scholar
  13. Rousse I, Robitaille R (2006) Calcium signaling in Schwann cells at synaptic and extra-synaptic sites: active glial modulation of neuronal activity. Glia 54:691–699CrossRefPubMedGoogle Scholar
  14. Shavit E, Beilin O, Korczyn AD, Sylantiev C, Aronovich R, Drory VE, Gurwitz D, Horresh I, Bar-Shavit R, Peles E, Chapman J (2008) Thrombin receptor PAR-1 on myelin at the node of Ranvier: a new anatomy and physiology of conduction block. Brain 131(4):1113–1122CrossRefPubMedGoogle Scholar
  15. Smirnova IV, Ma JY, Citron BA, Ratzlaff KT, Gregory EJ, Akaaboune M et al (1996) Neural thrombin and protease nexin I kinetics after murine peripheral nerve injury. J Neurochem 67:2188–2199 Available from: CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Laboratory for Neurology Research Department of Neurology and the Joseph Sagol Neuroscience Center, Chaim Sheba Medical CenterTel HaShomerRamat GanIsrael
  2. 2.Department of Physical Therapy, Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  3. 3.Department of Neurology, Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  4. 4.Robert and Martha Harden Chair in Mental and Neurological Diseases, Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael

Personalised recommendations