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Effect of Spinal Cord Injury on P2 Signaling in the Cholinergic Synapse

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Abstract

Thoracic spinal cord injuries are well known to entail the degradation of spinal motoneurons, accompanied by axonal degeneration. In the present study, the functional integrity of neuromuscular transmission was assessed via stimulation mechanomiography in Wistar rats. We demonstrated a decrease in the modulating activity of ATP in the cholinergic synapse due to spinal cord injury (a model of spinal cord contusion injury) vs. hypodynamia (a model of anti-orthostatic hindlimb suspension). The revealed abnormal purine-mediated modulation of the neuromuscular junction provides evidence for axonal degeneration and suggests that trans-synaptic degeneration of motor neurons may occur below the spinal cord injury level in patients with similar traumas.

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REFERENCES

  1. Pollin MM, McHanwell S, Slater CR (1991) The effect of age on motor neurone death following axotomy in the mouse. Development 112 (1): 83–89. https://doi.org/10.1242/dev.112.1.83

    Article  CAS  PubMed  Google Scholar 

  2. Rishal I, Fainzilber M (2014) Axon-soma communication in neuronal injury. Nat Rev Neurosci 15(1): 32–42. https://doi.org/10.1038/nrn3609

    Article  CAS  PubMed  Google Scholar 

  3. Jackson AB, Dijkers M, Devivo MJ, Poczatek RB (2004) A demographic profile of new traumatic spinal cord injuries: change and stability over 30 years. Arch Phys Med Rehabil 85(11): 1740–1748. https://doi.org/10.1016/j.apmr.2004.04.035

    Article  PubMed  Google Scholar 

  4. Burns AS, Jawaid S, Zhong H, Yoshihara H, Bhagat S, Murray M, Roy RR, Tessler A, Son YJ (2007) Paralysis elicited by spinal cord injury evokes selective disassembly of neuromuscular synapses with and without terminal sprouting in ankle flexors of the adult rat. J Comp Neurol 500(1): 116–133. https://doi.org/10.1002/cne.21143

    Article  CAS  PubMed  Google Scholar 

  5. Burns AS, Lemay MA, Tessler A (2005) Abnormal spontaneous potentials in distal muscles in animal models of spinal cord injury. Muscle Nerve 31(1): 46–51. https://doi.org/10.1002/mus.20229

    Article  PubMed  Google Scholar 

  6. Kaelan C, Jacobsen PF, Kakulas BA (1988) An investigation of possible transynaptic neuronal degeneration in human spinal cord injury. J Neurol Sci 86(2–3): 231–237. https://doi.org/10.1016/0022-510x(88)90101-3

    Article  CAS  PubMed  Google Scholar 

  7. Bjugn R, Nyengaard JR, Rosland JH (1997) Spinal cord transection—no loss of distal ventral horn neurons. Modern stereological techniques reveal no transneuronal changes in the ventral horns of the mouse lumbar spinal cord after thoracic cord transection. Exp Neurol 148(1): 179–186.

    Article  PubMed  Google Scholar 

  8. Kirshblum S, Lim S, Garstang S, Millis S (2001) Electrodiagnostic changes of the lower limbs in subjects with chronic complete cervical spinal cord injury. Arch Phys Med Rehabil 82(5): 604–607. https://doi.org/10.1053/apmr.2001.22348

    Article  CAS  PubMed  Google Scholar 

  9. Burns AS, Boyce VS, Tessler A, Lemay MA (2007) Fibrillation potentials following spinal cord injury: Improvement with neurotrophins and exercise. Muscle Nerve 35(5): 607–613. https://doi.org/10.1002/mus.20738

    Article  CAS  PubMed  Google Scholar 

  10. Carter JG, Sokoll MD, Gergis SD (1981) Effect of spinal cord transection on neuromuscular function in the rat. Anesthesiology 55(5): 542–546. https://doi.org/10.1097/00000542-198111000-00011

    Article  CAS  PubMed  Google Scholar 

  11. Dahlstrom A, Heiwall PO, Booj S, Dahllof AG (1978) The influence of supraspinal impulse activity on the intra-axonal transport of acetylcholine, choline acetyltransferase and acetylcholinesterase in rat motor neurons. Acta Physiol Scand 103(3): 308–319. https://doi.org/10.1111/j.1748-1716.1978.tb06218.x

    Article  CAS  PubMed  Google Scholar 

  12. Akaaboune M, Culican SM, Turney SG, Lichtman JW (1999) Rapid and reversible effects of activity on acetylcholine receptor density at the neuromuscular junction in vivo. Science 286(5439): 503–507. https://doi.org/10.1126/science.286.5439.503

    Article  CAS  PubMed  Google Scholar 

  13. Bruneau E, Sutter D, Hume RI, Akaaboune M (2005) Identification of nicotinic acetylcholine receptor recycling and its role in maintaining receptor density at the neuromuscular junction in vivo. J Neurosci 25(43): 9949–9959. https://doi.org/10.1523/JNEUROSCI.3169-05.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Xiong GX, Zhang JW, Hong Y, Guan Y, Guan H (2008) Motor unit number estimation of the tibialis anterior muscle in spinal cord injury. Spinal Cord 46(10): 696–702. https://doi.org/10.1038/sc.2008.7

    Article  PubMed  Google Scholar 

  15. Cotrina ML, Lin JH, Alves-Rodrigues A, Liu S, Li J, Azmi-Ghadimi H, Kang J, Naus CC, Nedergaard M (1988) Connexins regulate calcium signaling by controlling ATP release. Proc Natl Acad Sci USA 95(26): 15735–15740. https://doi.org/10.1073/pnas.95.26.15735

    Article  Google Scholar 

  16. Guthrie PB, Knappenberger J, Segal M, Bennett MV, Charles AC, Kater SB (1999) ATP released from astrocytes mediates glial calcium waves. J Neurosci 19(2): 520–528. https://doi.org/10.1523/JNEUROSCI.19-02-00520.1999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Arcuino G, Lin JHC, Takano T, Liu C, Jiang L, Gao Q, Kang J, Nedergaard M (2002) Intercellular calcium signaling mediated by point-source burst release of ATP. Proc Natl Acad Sci USA 99(15): 9840–9845. https://doi.org/10.1073/pnas.152588599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fields RD, Stevens-Graham B (2002) New insights into neuron-glia communication. Science 298(5593): 556–562. https://doi.org/10.1126/science.298.5593.556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Haydon PG (2001) Glia: listening and talking to the synapse. Nat Rev Neurosci 2(3): 185–193. https://doi.org/10.1038/35058528

    Article  CAS  PubMed  Google Scholar 

  20. Nedergaard M, Ransom B, Goldman S (2003) New roles for astrocytes: Redefining the functional architecture of the brain. Trends Neurosci 26(10): 523–530. https://doi.org/10.1016/j.tins.2003.08.008

    Article  CAS  PubMed  Google Scholar 

  21. Fam SR, Gallagher CJ, Salter MW (2000) P2Y(1) purinoceptor-mediated Ca2+ signaling and Ca2+ wave propagation in dorsal spinal cord astrocytes. J Neurosci 20(8): 2800–2808. https://doi.org/10.1523/JNEUROSCI.20-08-02800.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Khakh BS, North RA (2006) P2X receptors as cell-surface ATP sensors in health and disease. Nature 442(7102): 527–532. https://doi.org/10.1038/nature04886

    Article  CAS  PubMed  Google Scholar 

  23. Gourine AV, Dale N, Llaudet E, Poputnikov DM, Spyer KM, Gourine VN (2007) Release of ATP in the central nervous system during systemic inflammation: Real-time measurement in the hypothalamus of conscious rabbits. J Physiol 585(Pt 1): 305–316. https://doi.org/10.1113/jphysiol.2007.143933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang X, Arcuino G, Takano T, Lin J, Peng WG, Wan P, Li P, Xu Q, Liu QS, Goldman SA, Nedergaard M (2004) P2X7 receptor inhibition improves recovery after spinal cord injury. Nature Med 10(8): 821–827. https://doi.org/10.1038/nm1082

    Article  CAS  PubMed  Google Scholar 

  25. North A (2002) Molecular physiology of P2X receptors. Physiol Rev 82(4): 1013–1067. https://doi.org/10.1152/physrev.00015.2002

    Article  CAS  PubMed  Google Scholar 

  26. Solle M, Labasi J, Perregaux DG, Stam E, Petrushova N, Koller BH, Griffiths RJ, Gabel CA (2001) Altered cytokine production in mice lacking P2X7 receptors. J Biol Chem 276(1): 125–132. https://doi.org/10.1074/jbc.M006781200

    Article  CAS  PubMed  Google Scholar 

  27. Kahlenberg J, Dubyak GW (2004) Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ release. Am J Physiol 286(5): 1100–1108. https://doi.org/10.1152/ajpcell.00494.2003

    Article  Google Scholar 

  28. Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, Bonventre JV, Woolf CJ (2001) Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 410(6827): 471–475. https://doi.org/10.1038/35068566

    Article  CAS  PubMed  Google Scholar 

  29. Suzuki T, Hide I, Ido K, Kohsaka S, Inoue K, Nakata Y (2004) Production and release of neuroprotective tumor necrosis factor by P2X7 receptor-activated microglia. J Neurosci 24(1): 1–7. https://doi.org/10.1523/JNEUROSCI.13-12-05153.1993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Allen AR (1911) Surgery of experimental lesion of spinal cord equivalent to crush injury of fracture dislocation of spinal column: a preliminary report. JAMA 57: 878–880.

    Article  Google Scholar 

  31. Ilyin EA, Novikov VE (1980) Stand for modeling the physiological effects of weightlessness in laboratory experiments with rats. Cosm biol aerocosm med 14(3): 79–80. (In Russ).

    Google Scholar 

  32. Morey-Holton ER, Globus RK (2002) Hindlimb unloading rodent model: technical aspects. J Appl Physiol 92(4): 1367–1377. https://doi.org/10.1152/japplphysiol.00969.2001

    Article  PubMed  Google Scholar 

  33. Morey-Holton ER, Globus RK (1988) Hindlimb unloading of growing rats: a model for predicting skeletal changes during space flight. Bone 22(5 Suppl): 83–88. https://doi.org/10.1016/s8756-3282(98)00019-2

    Article  Google Scholar 

  34. Khairullin AE, Efimova DV, Markosyan VA, Grishin SN, Teplov AY, Ziganshin AU (2021) The effect of acute unilateral denervation injury on purinergic signaling in the cholinergic synapse. Biophysics 66(3): 483–486. https://doi.org/10.1134/S0006350921030064

    Article  CAS  Google Scholar 

  35. Profyris C, Cheema SS, Zang DW, Azari MF, Boyle K, Petratos S (2004) Degenerative and regenerative mechanisms governing spinal cord injury. Neurobiol Disease 15(3): 415–436. https://doi.org/10.1016/j.nbd.2003.11.015

    Article  Google Scholar 

  36. Beattie MS, Farooqui AA, Bresnahan JC (2000) Review of current evidence for apoptosis after spinal cord injury. J Neurotrauma 17(10): 915–925. https://doi.org/10.1089/neu.2000.17.915

    Article  CAS  PubMed  Google Scholar 

  37. Peng W, Cotrina ML, Han X, Yu H, Bekar L, Blum L, Takano T, Tian GF, Goldman SA, Nedergaard M (2009) Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury. Proc Natl Acad Sci USA 106(30): 12489–12493. https://doi.org/10.1073/pnas.0902531106

    Article  PubMed  PubMed Central  Google Scholar 

  38. Grafe P, Schaffer V, Rucker F (2006) Kinetics of ATP release following compression injury of a peripheral nerve trunk. Purinerg Signal 2: 527–536.

    Article  CAS  Google Scholar 

  39. Cook SP, McCleskey EW (2002) Cell damage excites nociceptors through release of cytosolic ATP. Pain 95(1–2): 41–47.

    Article  CAS  PubMed  Google Scholar 

  40. Neary JT, Kang Y, Willoughby KA, Ellis EF (2003) Activation of extracellular signal- regulated kinase by stretch-induced injury in astrocytes involves extracellular ATP and P2 purinergic receptors. J Neurosci 23(6): 2348–2356. https://doi.org/10.1523/JNEUROSCI.23-06-02348.2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Du S, Rubin A, Klepper S, Barrett C, Kim YC, Rhim HW, Lee EB, Park CW, Markelonis GJ, Oh TH (1999) Calcium influx and activation of calpain I mediate acute reactive gliosis in injured spinal cord. Exp Neurol 157(1): 96–105. https://doi.org/10.1006/exnr.1999.7041

    Article  CAS  PubMed  Google Scholar 

  42. Stokes BT, Fox P, Hollinden G (1983) Extracellular calcium activity in the injured spinal cord. Exp Neurol 80(3): 561–572.

    Article  CAS  PubMed  Google Scholar 

  43. Nilsson P, Hillered L, Olsson Y, Sheardown MJ, Hansen AJ (1993) Regional changes in interstitial K+ and Ca2+ levels following cortical compression contusion trauma in rats. J Cereb Blood Flow Metab 13(2): 183–192. https://doi.org/10.1038/jcbfm.1993.22

    Article  CAS  PubMed  Google Scholar 

  44. Stout C, Charles A (2003) Modulation of intercellular calcium signaling in astrocytes by extracellular calcium and magnesium. Glia 43(3): 265–273. https://doi.org/10.1002/glia.10257

    Article  PubMed  Google Scholar 

  45. Bianchi BR, Lynch KJ, Touma E, Niforatos W, Burgard EC, Alexander KM, Park HS, Yu H, Metzger R, Kowaluk E, Jarvis MF, Biesen T (1999) Pharmacological characterization of recombinant human and rat P2X receptor subtypes. Eur J Pharmacol 376(1-2): 127–138. https://doi.org/10.1002/glia.10257

    Article  CAS  PubMed  Google Scholar 

  46. Di Virgilio, Chiozzi FP, Falzoni S, Ferrari D, Sanz JM, Venketaraman V, Baricordi OR (1998) Cytolytic P2X purinoceptors. Cell Death Differ 5(3): 191–199.

    Article  Google Scholar 

  47. Deuchars SA, Atkinson L, Brooke RE, Musa H, Milligan CJ, Batten TF, Buckley NJ, Parson SH, Deuchars J (2001) Neuronal P2X7 receptors are targeted to presynaptic terminals in the central and peripheral nervous systems. J Neurosci 21(18): 7143–7152. https://doi.org/10.1523/JNEUROSCI.21-18-07143.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gerasimenko YP, Avelev VD, Nikitin OA, Lavrov IA (2003) Initiation of locomotor activity in spinal cats by epidural stimulation of the spinal cord. Neurosci Behav Physiol 33(3): 247–254. https://doi.org/10.1023/a:1022199214515

    Article  PubMed  Google Scholar 

  49. Lavrov I, Dy CJ, Fong AJ, Gerasimenko Y, Courtine G, Zhong H, Roy RR, Edgerton VR (2008) Epidural stimulation induced modulation of spinal locomotor networks in adult spinal rats. J Neurosci 28(23): 6022–6029. https://doi.org/10.1523/JNEUROSCI.0080-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Irnich D, Burgstahler R, Bostock H, Grafe P (2001) ATP affects both axons and Schwann cells of unmyelinated C fibers. Pain 92: 343–350. https://doi.org/10.1016/S0304-3959(01)00277-9

    Article  CAS  PubMed  Google Scholar 

  51. Lucas DR, Newhouse JP (1957) The Toxic Effect of Sodium L-Glutamate on the Inner Layers of the Retina. AMA Archiv Ophthalmol 58(2): 193–201. https://doi.org/10.1001/archopht.1957.00940010205006

    Article  CAS  Google Scholar 

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Funding

This work was supported by the grant 2/22-5 to Kazan State Medical University, Ministry of Health Care of Russia, for the implementation of scientific research within the University Development Program and as part of the Strategic Academic Leadership of Kazan Federal University (PRIORITY-2030).

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All authors equally contributed to conceptualization and design of the study, as well as data collection and processing, writing and editing the manuscript.

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Correspondence to A. E. Khairullin.

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COMPLIANCE WITH ETHICAL STANDARDS

The experiments were carried out in compliance with current ethical standards. All applicable international, national and/or institutional principles of animal care and use were observed. All the procedures that involved laboratory animals met the ethical standards approved by the legal acts of the Russian Federation and principles of the Basel Declaration.

CONFLICT OF INTEREST

The authors declare that they have no conflict of interest.

Additional information

Translated by A. Polyanovsky

Russian Text © The Author(s), 2023, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2023, Vol. 109, No. 5, pp. 588–599https://doi.org/10.31857/S0869813923050059.

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Khairullin, A.E., Efimova, D.V., Eremeev, A.A. et al. Effect of Spinal Cord Injury on P2 Signaling in the Cholinergic Synapse. J Evol Biochem Phys 59, 822–830 (2023). https://doi.org/10.1134/S0022093023030158

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