Skip to main content

Advertisement

SpringerLink
Log in

Methylmercury reduces synaptic transmission and neuronal excitability in rat hippocampal slices

  • Ion channels, receptors and transporters
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

In a previous study, we pointed out that the neurotoxic action evoked by methylmercury (MeHg), a potent environmental pollutant responsible for fatal food poisoning, is associated with alterations of cellular excitability by irreversible blockade of sodium and calcium currents. Here, we investigated the MeHg effects on synaptic transmission and neuronal plasticity using extracellular field recording in CA1 area of rat hippocampal slices. MeHg caused a fast and drastic depression of evoked field excitatory postsynaptic potentials (fEPSPs) in a concentration-dependent manner with an IC50 of 25.7 μM. This depression was partially caused by the irreversible reduction of axon recruitment deduced from the decrement of the fiber volley (FV) amplitude. Nevertheless, this MeHg-induced synaptic depression represents a true reduction of synaptic efficacy, as judged by input/output curves. In addition, a reduction on presynaptic release of glutamate was detected with the paradigm of paired-pulse facilitation during MeHg application. Moreover, MeHg also reduced population spike (PS) ampxlitude, and this effect was more prominent when the PS was evoked by ortodromic stimulation than by antidromic stimulation. Interestingly, despite these strong effects of MeHg on synaptic transmission and excitability, this compound did not modify the induction of long-term synaptic potentiation (LTP). The effects described here for MeHg were irreversible or very slowly reversible after drug wash-out. In summary, the blockade of sodium and calcium channels by MeHg affects synaptic transmission and cellular excitability but not synaptic plasticity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Andersen P (1960) Interhippocampal impulses. 2. Apical dendritic activation of CAL neurons. AFOSR TN United States Air Force Off Sci Res 59:998–991

    PubMed  CAS  Google Scholar 

  2. Aschner M, Aschner JL (1990) Mercury neurotoxicity: mechanisms of blood-brain barrier transport. Neurosci Biobehav Rev 14(2):169–176

    Article  PubMed  CAS  Google Scholar 

  3. Atchison WD (2005) Is chemical neurotransmission altered specifically during methylmercury-induced cerebellar dysfunction? Trends Pharmacol Sci 26(11):549–557

    Article  PubMed  CAS  Google Scholar 

  4. Atchison WD, Hare MF (1994) Mechanisms of methylmercury-induced neurotoxicity. FASEB J 8(9):622–629

    Article  PubMed  CAS  Google Scholar 

  5. Atchison WD, Narahashi T (1982) Methylmercury-induced depression of neuromuscular transmission in the rat. Neurotoxicology 3(3):37–50

    PubMed  CAS  Google Scholar 

  6. Bakir F, Damluji SF, Amin-Zaki L, Murtadha M, Khalidi A, al-Rawi NY, Tikriti S, Dhahir HI, Clarkson TW, Smith JC, Doherty RA (1973) Methylmercury poisoning in Iraq. Science 181(4096):230–241

    Article  PubMed  CAS  Google Scholar 

  7. Baldelli P, Forni PE, Carbone E (2000) BDNF, NT-3 and NGF induce distinct new Ca2+ channel synthesis in developing hippocampal neurons. Eur J Neurosci 12(11):4017–4032

    Article  PubMed  CAS  Google Scholar 

  8. Bliss T, Lømo T (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol 232:331–356

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Burgoyne RD, Alvarez de Toledo G (2000) Fusion proteins and fusion pores. Workshop: regulated exocytosis and the vesicle cycle. EMBO Rep 1(4):304–307

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Carocci A1, Rovito N, Sinicropi MS, Genchi G (2014) Mercury toxicity and neurodegenerative effects. Rev Environ Contam Toxicol 229:1–18

    PubMed  CAS  Google Scholar 

  11. Eyl TB (1971) Organic-mercury food poisoning. N Engl J Med 284(13):706–709

    Article  PubMed  CAS  Google Scholar 

  12. Falluel-Morel A, Lin L, Sokolowski K, McCandlish E, Buckley B, DiCicco-Bloom E (2012) N-Acetyl cysteine treatment reduces mercury-induced neurotoxicity in the developing rat hippocampus. J Neurosci Res 90(4):743–750

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Fountain SB, Rowan JD (2000) Effects of sequential exposure to multiple concentrations of methylmercury in the rat hippocampal slice. Ecotox Environ Safe 47(2):130–136

    Article  CAS  Google Scholar 

  14. Franco JL, Posser T, Dunkley PR, Dickson PW, Mattos JJ, Martins R, Bainy ACD, Marques MR, Dafre AL, Farina M (2009) Methylmercury neurotoxicity is associated with inhibition of the antioxidant enzyme glutathione peroxidase. Free Radic Biol Med 47(4):449–457

    Article  PubMed  CAS  Google Scholar 

  15. Friberg L, Mottet NK (1989) Accumulation of methylmercury and inorganic mercury in the brain. Biol Trace Elem Res 21:201–206

    Article  PubMed  CAS  Google Scholar 

  16. Fuentes-Antras J, Osorio-Martinez E, Ramirez-Torres M, Colmena I, Fernandez-Morales JC, Hernandez-Guijo JM (2013) Methylmercury decreases cellular excitability by a direct blockade of sodium and calcium channels in bovine chromaffin cells: an integrative study. Pflugers Arch 465(12):1727–1740

    Article  PubMed  CAS  Google Scholar 

  17. Hajela RK, Peng SQ, Atchison WD (2003) Comparative effects of methylmercury and Hg(2+) on human neuronal N- and R-type high-voltage activated calcium channels transiently expressed in human embryonic kidney 293 cells. J Pharmacol Exp Ther 306(3):1129–1136

    Article  PubMed  CAS  Google Scholar 

  18. Hess G, Kuhnt U (1992) Presynaptic calcium transients evoked by paired-pulse stimulation in the hippocampal slice. Neuroreport 3(4):361–364

    Article  PubMed  CAS  Google Scholar 

  19. Hodgkin AL, Huxley AF (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol 117(4):500–544

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Katz B, Miledi R (1968) The role of calcium in neuromuscular facilitation. J Physiol 195(2):481–492

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Leonhardt R, Haas H, Büsselberg D (1996) Methyl mercury reduces voltage-activated currents of rat dorsal root ganglion neurons. Naunyn Schmiedeberg’s Arch Pharmacol 354(4):532–538

  22. Leonhardt R, Pekel M, Platt B, Haas HL, Busselberg D (1996) Voltage-activated calcium channel currents of rat DRG neurons are reduced by mercuric chloride (HgCl2) and methylmercury (CH3HgCl). Neurotoxicology 17(1):85–92

    PubMed  CAS  Google Scholar 

  23. Manabe T, Wyllie DJ, Perkel DJ, Nicoll RA (1993) Modulation of synaptic transmission and long-term potentiation: effects on paired pulse facilitation and EPSC variance in the CA1 region of the hippocampus. J Neurophysiol 70(4):1451–1459

    Article  PubMed  CAS  Google Scholar 

  24. Mancini JD, Autio DM, Atchison WD (2009) Continuous exposure to low concentrations of methylmercury impairs cerebellar granule cell migration in organotypic slice culture. Neurotoxicology 30(2):203–208

    Article  PubMed  CAS  Google Scholar 

  25. Merad-Boudia M, Nicole A, Santiard-Baron D, Saillé C, Ceballos-Picot I (1998) Mitochondrial impairment as an early event in the process of apoptosis induced by glutathione depletion in neuronal cells: relevance to Parkinson’s disease. Biochem Pharmacol 56(5):645–655

    Article  PubMed  CAS  Google Scholar 

  26. Myers GJ, Davidson PW (1998) Prenatal methylmercury exposure and children: neurologic, developmental, and behavioral research. Environ Health Perspect 106(Suppl 3):841–847

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ochi T (2002) Methylmercury, but not inorganic mercury, causes abnormality of centrosome integrity (multiple foci of gamma-tubulin), multipolar spindles and multinucleated cells without microtubule disruption in cultured Chinese hamster V79 cells. Toxicology 175(1–3):111–121

    Article  PubMed  CAS  Google Scholar 

  28. Peng S, Hajela RK, Atchison WD (2002) Effects of methylmercury on human neuronal L-type calcium channels transiently expressed in human embryonic kidney cells (HEK-293). J Pharmacol Exp Ther 302(2):424–432

    Article  PubMed  CAS  Google Scholar 

  29. Protti DA, Uchitel OD (1993) Transmitter release and presynaptic Ca2+ currents blocked by the spider toxin omega-Aga-IVA. Neuroreport 5(3):333–336

    Article  PubMed  CAS  Google Scholar 

  30. Quandt FN, Kato E, Narahashi T (1982) Effects of methylmercury on electrical responses of neuroblastoma cells. Neurotoxicology 3(4):205–220

    PubMed  CAS  Google Scholar 

  31. Raastad M, Shepherd GM (2003) Single-axon action potentials in the rat hippocampal cortex. J Physiol 548(Pt 3):745–752

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Rao MV, Purohit A, Patel T (2010) Melatonin protection on mercury-exerted brain toxicity in the rat. Drug Chem Toxicol 33(2):209–216

    Article  PubMed  CAS  Google Scholar 

  33. Roda E, Coccini T, Acerbi D, Castoldi A, Bernocchi G, Manzo L (2008) Cerebellum cholinergic muscarinic receptor (subtype-2 and -3) and cytoarchitecture after developmental exposure to methylmercury: an immunohistochemical study in rat. J Chem Neuroanat 35(3):285–294

    Article  PubMed  CAS  Google Scholar 

  34. Sakaue M, Mori N, Makita M, Fujishima K, Hara S, Arishima K, Yamamoto M (2009) Acceleration of methylmercury-induced cell death of rat cerebellar neurons by brain-derived neurotrophic factor in vitro. Brain Res 1273:155–162

    Article  PubMed  CAS  Google Scholar 

  35. Sarafian T, Verity MA (1991) Oxidative mechanisms underlying methyl mercury neurotoxicity. Int J Dev Neurosci 9(2):147–153

    Article  PubMed  CAS  Google Scholar 

  36. Shafer TJ, Atchison WD (1992) Effects of methylmercury on perineurial Na+ and Ca2+-dependent potentials at neuromuscular junctions of the mouse. Brain Res 595(2):215–219

    Article  PubMed  CAS  Google Scholar 

  37. Sirois JE, Atchison WD (2000) Methylmercury affects multiple subtypes of calcium channels in rat cerebellar granule cells. Toxicol Appl Pharmacol 167(1):1–11

    Article  PubMed  CAS  Google Scholar 

  38. Szucs A, Angiello C, Salanki J, Carpenter DO (1997) Effects of inorganic mercury and methylmercury on the ionic currents of cultured rat hippocampal neurons. Cell Mol Neurobiol 17(3):273–288

    Article  PubMed  CAS  Google Scholar 

  39. Takahashi T, Momiyama A (1993) Different types of calcium channels mediate central synaptic transmission. Nature 366(6451):156–158

    Article  PubMed  CAS  Google Scholar 

  40. Takeuchi T (1982) Pathology of Minamata disease. With special reference to its pathogenesis. Acta Pathol Jpn 32(Suppl 1):73–99

    PubMed  Google Scholar 

  41. Yuan Y, Atchison WD (1993) Disruption by methylmercury of membrane excitability and synaptic transmission of CA1 neurons in hippocampal slices of the rat. Toxicol Appl Pharmacol 120(2):203–215

    Article  PubMed  CAS  Google Scholar 

  42. Yuan Y, Atchison WD (1995) Methylmercury acts at multiple sites to block hippocampal synaptic transmission. J Pharmacol Exp Ther 275(3):1308–1316

    PubMed  CAS  Google Scholar 

  43. Yuan Y, Atchison WD (1997) Action of methylmercury on GABA(A) receptor-mediated inhibitory synaptic transmission is primarily responsible for its early stimulatory effects on hippocampal CA1 excitatory synaptic transmission. J Pharmacol Exp Ther 282(1):64–73

    PubMed  CAS  Google Scholar 

  44. Yuan Y, Atchison WD (2007) Methylmercury-induced increase of intracellular Ca2+ increases spontaneous synaptic current frequency in rat cerebellar slices. Mol Pharmacol 71(4):1109–1121

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

G.J. is a fellow of MEC. E.A. is a fellow of FTH. The authors gratefully acknowledge the technical assistance of José Barbado.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Therapeutic, Universidad Autónoma de Madrid, IRYCIS, Av. Arzobispo Morcillo 4, 28029, Madrid, Spain

    J. Gutiérrez, A. M. Baraibar, E. Albiñana, P. Velasco & J. M. Hernández-Guijo

  2. Instituto Teófilo Hernando, Facultad de Medicina, Departamento de Farmacología, Universidad Autónoma de Madrid, IRYCIS, Av. Arzobispo Morcillo 4, 28029, Madrid, Spain

    J. Gutiérrez, A. M. Baraibar, E. Albiñana & J. M. Hernández-Guijo

  3. Servicio de Neurobiología-Investigación, Hospital Universitario Ramón y Cajal, IRYCIS, 28034, Madrid, Spain

    J. M. Solís

Authors
  1. J. Gutiérrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. M. Baraibar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Albiñana
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. Velasco
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. M. Solís
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. M. Hernández-Guijo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. M. Hernández-Guijo.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gutiérrez, J., Baraibar, A.M., Albiñana, E. et al. Methylmercury reduces synaptic transmission and neuronal excitability in rat hippocampal slices. Pflugers Arch - Eur J Physiol 470, 1221–1230 (2018). https://doi.org/10.1007/s00424-018-2144-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-018-2144-x

Keywords

Search

Navigation