Advertisement

Journal of Computational Neuroscience

, Volume 47, Issue 2–3, pp 167–189 | Cite as

Spontaneous synaptic drive in detrusor smooth muscle: computational investigation and implications for urinary bladder function

  • Nilapratim Sengupta
  • Rohit ManchandaEmail author
Article
  • 39 Downloads

Abstract

The detrusor, a key component of the urinary bladder wall, is a densely innervated syncytial smooth muscle tissue. Random spontaneous release of neurotransmitter at neuromuscular junctions (NMJs) in the detrusor gives rise to spontaneous excitatory junction potentials (SEJPs). These sub-threshold passive signals not only offer insights into the syncytial nature of the tissue, their spatio-temporal integration is critical to the generation of spontaneous neurogenic action potentials which lead to focal contractions during the filling phase of the bladder. Given the structural complexity and the contractile nature of the tissue, electrophysiological investigations on spatio-temporal integration of SEJPs in the detrusor are technically challenging. Here we report a biophysically constrained computational model of a detrusor syncytium overlaid with spatially distributed innervation, using which we explored salient features of the integration of SEJPs in the tissue and the key factors that contribute to this integration. We validated our model against experimental data, ascertaining that observations were congruent with theoretical predictions. With the help of comparative studies, we propose that the amplitude of the spatio-temporally integrated SEJP is most sensitive to the inter-cellular coupling strength in the detrusor, while frequency of observed events depends more strongly on innervation density. An experimentally testable prediction arising from our study is that spontaneous release frequency of neurotransmitter may be implicated in the generation of detrusor overactivity. Set against histological observations, we also conjecture possible changes in the electrical activity of the detrusor during pathology involving patchy denervation. Our model thus provides a physiologically realistic, heuristic framework to investigate the spread and integration of passive potentials in an innervated syncytial tissue under normal conditions and in pathophysiology.

Keywords

Spatio-temporal integration SEJP Syncytium Detrusor Synaptic drive Neurotransmission Smooth muscle Sub-threshold potentials Urinary bladder Computational model 

Notes

Acknowledgements

The work was supported by grants from the Department of Biotechnology (DBT), India (BT/PR12973/MED/122/47/2016) and the UK-India Education and Research Initiative, UKIERI (UKUTP20110055).

Compliance with ethical standards

Conflict of interest

None.

References

  1. Andersson, K. E., Chapple, C., & Wein, A. (2001). The basis for drug treatment of the overactive bladder. World Journal of Urology, 19(5), 294–298.PubMedCrossRefGoogle Scholar
  2. Appukuttan, S., Brain, K. L., & Manchanda, R. (2015). A computational model of urinary bladder smooth muscle syncytium. Journal of Computational Neuroscience, 38(1), 167–187.PubMedCrossRefGoogle Scholar
  3. Bennett, M. R. (1973). Structure and electrical properties of the autonomic neuromuscular junction. Philosophical Transactions of the Royal Society of London. B, Biological Sciences, 265(867), 25–34.PubMedCrossRefGoogle Scholar
  4. Brading, A. F. (1997). A myogenic basis for the overactive bladder. Urology, 50(6), 57–67.PubMedCrossRefGoogle Scholar
  5. Brading, A. F. (2005). Overactive bladder: Why it occurs. Women's Health Medicine, 2(6), 20–23.CrossRefGoogle Scholar
  6. Bramich, N. J., & Brading, A. F. (1996). Electrical properties of smooth muscle in the Guinea-pig urinary bladder. The Journal of Physiology, 492(1), 185–198.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Cash, S., & Yuste, R. (1998). Input summation by cultured pyramidal neurons is linear and position-independent. Journal of Neuroscience, 18(1), 10–15.PubMedCrossRefGoogle Scholar
  8. Cash, S., & Yuste, R. (1999). Linear summation of excitatory inputs by CA1 pyramidal neurons. Neuron, 22(2), 383–394.PubMedCrossRefGoogle Scholar
  9. Crane, G. J., Hines, M. L., & Neild, T. O. (2001). Simulating the spread of membrane potential changes in arteriolar networks. Microcirculation, 8(1), 33–43.PubMedCrossRefGoogle Scholar
  10. Drake, M. J., Gardner, B. P., & Brading, A. F. (2003). Innervation of the detrusor muscle bundle in neurogenic detrusor overactivity. BJU International, 91(7), 702–710.PubMedCrossRefGoogle Scholar
  11. Drake, M. J., Kanai, A., Bijos, D. A., Ikeda, Y., Zabbarova, I., Vahabi, B., & Fry, C. H. (2017). The potential role of unregulated autonomous bladder micromotions in urinary storage and voiding dysfunction; overactive bladder and detrusor underactivity. BJU International, 119(1), 22–29.PubMedCrossRefGoogle Scholar
  12. Fry, C. H., Cooklin, M., Birns, J., & Mundy, A. R. (1999). Measurement of intercellular electrical coupling in Guinea-pig detrusor smooth muscle. The Journal of Urology, 161(2), 660–664.PubMedCrossRefGoogle Scholar
  13. Fry, C. H., Sui, G. P., Severs, N. J., & Wu, C. (2004). Spontaneous activity and electrical coupling in human detrusor smooth muscle: Implications for detrusor overactivity? Urology, 63(3), 3–10.PubMedCrossRefGoogle Scholar
  14. Gabella, G. (1995). The structural relations between nerve fibres and muscle cells in the urinary bladder of the rat. Journal of Neurocytology, 24(3), 159–187.PubMedCrossRefGoogle Scholar
  15. Gabella, G. (2012). Cells of visceral smooth muscles. Journal of Smooth Muscle Research, 48(4), 65–95.PubMedCrossRefGoogle Scholar
  16. Goto, K., Millecchia, L. L., Westfall, D. P., & Fleming, W. W. (1977). A comparison of the electrical properties and morphological characteristics of the smooth muscle of the rat and Guinea-pig vas deferens. Pflügers Archiv, 368(3), 253–261.PubMedCrossRefGoogle Scholar
  17. Hashitani, H. B. N. J., Bramich, N. J., & Hirst, G. D. S. (2000). Mechanisms of excitatory neuromuscular transmission in the Guinea-pig urinary bladder. The Journal of Physiology, 524(2), 565–579.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Hashitani, H., Fukuta, H., Takano, H., Klemm, M. F., & Suzuki, H. (2001). Origin and propagation of spontaneous excitation in smooth muscle of the Guinea-pig urinary bladder. The Journal of Physiology, 530(2), 273–286.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Hashitani, H., Brading, A. F., & Suzuki, H. (2004a). Correlation between spontaneous electrical, calcium and mechanical activity in detrusor smooth muscle of the Guinea-pig bladder. British Journal of Pharmacology, 141(1), 183–193.PubMedCrossRefGoogle Scholar
  20. Hashitani, H., Yanai, Y., & Suzuki, H. (2004b). Role of interstitial cells and gap junctions in the transmission of spontaneous Ca2+ signals in detrusor smooth muscles of the Guinea-pig urinary bladder. The Journal of Physiology, 559(2), 567–581.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Hayase, M., Hashitani, H., Kohri, K., & Suzuki, H. (2009). Role of K+ channels in regulating spontaneous activity in detrusor smooth muscle in situ in the mouse bladder. The Journal of Urology, 181(5), 2355–2365.PubMedCrossRefGoogle Scholar
  22. Inoue, R., & Brading, A. F. (1990). The properties of the ATP-induced depolarization and current in single cells isolated from the Guinea-pig urinary bladder. British Journal of Pharmacology, 100(3), 619–625.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Johnston, L., Cunningham, R. M., Young, J. S., Fry, C. H., McMurray, G., Eccles, R., & McCloskey, K. D. (2012). Altered distribution of interstitial cells and innervation in the rat urinary bladder following spinal cord injury. Journal of Cellular and Molecular Medicine, 16(7), 1533–1543.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Krasnoperov, V. G., Bittner, M. A., Beavis, R., Kuang, Y., Salnikow, K. V., Chepurny, O. G., Little, A. R., Plotnikov, A. N., Wu, D., Holz, R. W., & Petrenko, A. G. (1997). α-Latrotoxin stimulates exocytosis by the interaction with a neuronal G-protein-coupled receptor. Neuron, 18(6), 925–937.PubMedCrossRefGoogle Scholar
  25. Mahapatra, C., Brain, K. L., & Manchanda, R. (2018). A biophysically constrained computational model of the action potential of mouse urinary bladder smooth muscle. PLoS One, 13(7), e0200712.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Manchanda, R. (1995). Membrane current and potential change during neurotransmission in smooth muscle. Current Science, 69(2), 140–150.Google Scholar
  27. Manchanda, R., Appukuttan, S., & Padmakumar, M. (2019). Electrophysiology of syncytial smooth muscle. Journal of Experimental Neuroscience, 13, 1179069518821917.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Meng, E., Young, J. S., & Brading, A. F. (2008). Spontaneous activity of mouse detrusor smooth muscle and the effects of the urothelium. Neurourology and Urodynamics: Official Journal of the International Continence Society, 27(1), 79–87.CrossRefGoogle Scholar
  29. Neuhaus, J., Wolburg, H., Hermsdorf, T., Stolzenburg, J.-U., & Dorschner, W. (2002). Detrusor smooth muscle cells of the Guinea-pig are functionally coupled via gap junctions in situ and in cell culture. Cell and Tissue Research, 309(2), 301–311.PubMedCrossRefGoogle Scholar
  30. Padmakumar, M., Brain, K. L., Young, J. S., & Manchanda, R. (2018). A four-component model of the action potential in mouse detrusor smooth muscle cell. PLoS One, 13(1), e0190016.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Palani, D., & Manchanda, R. (2006). Effect of heptanol on noradrenaline-induced contractions in rat vas deferens. Journal of Smooth Muscle Research, 42(1), 49–61.Google Scholar
  32. Palani, D., Ghildyal, P., & Manchanda, R. (2006). Effects of carbenoxolone on syncytial electrical properties and junction potentials of Guinea-pig vas deferens. Naunyn-Schmiedeberg's Archives of Pharmacology, 374(3), 207–214.PubMedCrossRefGoogle Scholar
  33. Poirazi, P., Brannon, T., & Mel, B. W. (2003). Arithmetic of subthreshold synaptic summation in a model CA1 pyramidal cell. Neuron, 37(6), 977–987.PubMedCrossRefGoogle Scholar
  34. Sengupta, N., Brain, K. L., & Manchanda, R. (2015, August). Spatiotemporal dynamics of synaptic drive in urinary bladder syncytium: A computational investigation. In 2015 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) (pp. 8074–8077). IEEE.Google Scholar
  35. Sengupta, N., Brain, L. K., & Manchanda, R. (2018, July). Cellular Environment in a Bundle Modulates SEJP Characteristics in Detrusor Smooth Muscle. In 2018 40th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) (pp. 5842–5845). IEEE.Google Scholar
  36. Sourav, S., & Manchanda, R. (2000). Influence of the size of syncytial units on synaptic potentials in smooth muscle. Medical and Biological Engineering and Computing, 38(3), 356–359.PubMedCrossRefGoogle Scholar
  37. Tomita, T. (1976). Electrophysiology of mammalian smooth muscle. Progress in Biophysics and Molecular Biology, 30, 185–203.CrossRefGoogle Scholar
  38. Wang, H. Z., Brink, P. R., & Christ, G. J. (2006). Gap junction channel activity in short-term cultured human detrusor myocyte cell pairs: Gating and unitary conductances. American Journal of Physiology-Cell Physiology, 291(6), C1366–C1376.PubMedCrossRefGoogle Scholar
  39. Wüst, M., Averbeck, B., Reif, S., Bräter, M., & Ravens, U. (2002). Different responses to drugs against overactive bladder in detrusor muscle of pig, Guinea pig and mouse. European Journal of Pharmacology, 454(1), 59–69.PubMedCrossRefGoogle Scholar
  40. Young, J. S., Brain, K. L., & Cunnane, T. C. (2007). The origin of the skewed amplitude distribution of spontaneous excitatory junction potentials in poorly coupled smooth muscle cells. Neuroscience, 145(1), 153–161.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Young, J. S., Meng, E., Cunnane, T. C., & Brain, K. L. (2008). Spontaneous purinergic neurotransmission in the mouse urinary bladder. The Journal of Physiology, 586(23), 5743–5755.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Department of Biosciences and BioengineeringIndian Institute of Technology BombayMumbaiIndia

Personalised recommendations