Skip to main content
SpringerLink
Log in

Alterations in the Properties of the Rat Hippocampus Glutamatergic System in the Lithium-Pilocarpine Model of Temporal Lobe Epilepsy

  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

Status epilepticus (SE) triggers many not yet fully understood pathological changes in the nervous system that can lead to the development of epilepsy. In this work, we studied the effects of SE on the properties of excitatory glutamatergic transmission in the hippocampus in the lithium-pilocarpine model of temporal lobe epilepsy in rats. The studies were performed 1 day (acute phase), 3 and 7 days (latent phase), and 30 to 80 days (chronic phase) after SE. According to RT-qPCR data, expression of the genes coding for the AMPA receptor subunits GluA1 and GluA2 was downregulated in the latent phase, which may lead to the increased proportion of calcium-permeable AMPA receptors that play an essential role in the pathogenesis of many CNS diseases. The efficiency of excitatory synaptic neurotransmission in acute brain slices was decreased in all phases of the model, as determined by recording field responses in the CA1 region of the hippocampus in response to the stimulation of Schaffer collaterals by electric current of different strengths. However, the frequency of spontaneous excitatory postsynaptic potentials increased in the chronic phase, indicating an increased background activity of the glutamatergic system in epilepsy. This was also evidenced by a decrease in the threshold current causing hindlimb extension in the maximal electroshock seizure threshold test in rats with temporal lobe epilepsy compared to the control animals. The results suggest a series of functional changes in the properties of glutamatergic system associated with the epilepsy development and can be used to develop the antiepileptogenic therapy.

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.
Fig. 7.

Similar content being viewed by others

Abbreviations

EPSP:

excitatory postsynaptic potential

fPSP:

field postsynaptic potential

FV:

fiber volley

MEST:

maximal electroshock threshold

PS:

population spike

SE:

status epilepticus

SRS:

spontaneous recurrent seizure

TLE:

temporal lobe epilepsy

References

  1. Fattorusso, A., Matricardi, S., Mencaroni, E., Dell’Isola, G. B., Di Cara, G., Striano, P., and Verrotti, A. (2021) The pharmacoresistant epilepsy: an overview on existant and new emerging therapies, Front. Neurol., 12, 1030, https://doi.org/10.3389/FNEUR.2021.674483.

    Article  Google Scholar 

  2. Chin, J. H., and Vora, N. (2014) The global burden of neurologic diseases, J. Neurol., 83, 349-351, https://doi.org/10.1212/WNL.0000000000000610.

    Article  Google Scholar 

  3. Fordington, S., and Manford, M. (2020) A review of seizures and epilepsy following traumatic brain injury, J. Neurol., 267, 3105-3111, https://doi.org/10.1007/s00415-020-09926-w.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Engel, J. J. (2001) Mesial temporal lobe epilepsy: what have we learned?, Neuroscientist, 7, 340-352, https://doi.org/10.1177/107385840100700410.

    Article  PubMed  Google Scholar 

  5. Herman, S. T. (2002) Epilepsy after brain insult: targeting epileptogenesis, J. Neurol., 59, S21-S26, https://doi.org/10.1212/wnl.59.9_suppl_5.s21.

    Article  Google Scholar 

  6. Pitkänen, A., and Lukasiuk, K. (2011) Mechanisms of epileptogenesis and potential treatment targets, Lancet Neurol., 10, 173-186, https://doi.org/10.1016/S1474-4422(10)70310-0.

    Article  PubMed  Google Scholar 

  7. Goldberg, E. M., and Coulter, D. A. (2013) Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction, Nat. Rev. Neurosci., 14, 337-349, https://doi.org/10.1038/nrn3482.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Thom, M. (2014) Review: hippocampal sclerosis in epilepsy: a neuropathology review, Neuropathol. Appl. Neurobiol., 40, 520-543, https://doi.org/10.1111/nan.12150.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Bliss, T. V. P., and Collingridge, G. L. (1993) A synaptic model of memory: long-term potentiation in the hippocampus, Nature, 361, 31-39, https://doi.org/10.1038/361031a0.

    Article  CAS  PubMed  Google Scholar 

  10. Titiz, A. S., Mahoney, J. M., Testorf, M. E., Holmes, G. L., and Scott, R. C. (2014) Cognitive impairment in temporal lobe epilepsy: role of online and offline processing of single cell information, Hippocampus, 24, 1129-1145, https://doi.org/10.1002/hipo.22297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Vlooswijk, M. C. G., Jansen, J. F. A., de Krom, M. C. F. T. M., Majoie, H. M., Hofman, P. A. M., Backes, W. H., and Aldenkamp, A. P. (2010) Functional MRI in chronic epilepsy: associations with cognitive impairment, Lancet Neurol., 9, 1018-1027, https://doi.org/10.1016/S1474-4422(10)70180-0.

    Article  PubMed  Google Scholar 

  12. Zavala-Tecuapetla, C., Cuellar-Herrera, M., and Luna-Munguia, H. (2020) Insights into potential targets for therapeutic intervention in epilepsy, Int. J. Mol. Sci., 21, 8573, https://doi.org/10.3390/ijms21228573.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Curia, G., Longo, D., Biagini, G., Jones, R. S. G., and Avoli, M. (2008) The pilocarpine model of temporal lobe epilepsy, J. Neurosci. Methods, 172, 143-157, https://doi.org/10.1016/j.jneumeth.2008.04.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Curia, G., Lucchi, C., Vinet, J., Gualtieri, F., Marinelli, C., Torsello, A., Costantino, L., and Biagini, G. (2014) Pathophysiogenesis of mesial temporal lobe epilepsy: is prevention of damage antiepileptogenic?, Curr. Med. Chem., 21, 663-688, https://doi.org/10.2174/0929867320666131119152201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zaitsev, A. V., Amakhin, D. V., Dyomina, A. V., Zakharova, M. V., Ergina, J. L., Postnikova, T. Y., Diespirov, G. P., and Magazanik, L. G. (2021) Synaptic dysfunction in epilepsy, J. Evol. Biochem. Physiol., 57, 542-563, https://doi.org/10.1134/S002209302103008X.

    Article  Google Scholar 

  16. De Oliveira, D. L., Fischer, A., Jorge, R. S., Da Silva, M. C., Leite, M., Gonçalves, C. A., Quillfeldt, J. A., Souza, D. O., E Souza, T. M., and Wofchuk, S. (2008) Effects of early-life LiCl-Pilocarpine-induced status epilepticus on memory and anxiety in adult rats are associated with mossy fiber sprouting and elevated CSF S100B protein, Epilepsia, 49, 842-852, https://doi.org/10.1111/j.1528-1167.2007.01484.x.

    Article  CAS  PubMed  Google Scholar 

  17. Morimoto, K., Fahnestock, M., and Racine, R. J. (2004) Kindling and status epilepticus models of epilepsy: rewiring the brain, Prog. Neurobiol., 73, 1-60, https://doi.org/10.1016/j.pneurobio.2004.03.009.

    Article  CAS  PubMed  Google Scholar 

  18. Postnikova, T. Y., Diespirov, G. P., Amakhin, D. V., Vylekzhanina, E. N., Soboleva, E. B., and Zaitsev, A. V. (2021) Impairments of long-term synaptic plasticity in the hippocampus of young rats during the latent phase of the lithium-pilocarpine model of temporal lobe epilepsy, Int. J. Mol. Sci., 22, 13355, https://doi.org/10.3390/ijms222413355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Plata, A., Lebedeva, A., Denisov, P., Nosova, O., Postnikova, T. Y., Pimashkin, A., Brazhe, A., Zaitsev, A. V., Rusakov, D. A., and Semyanov, A. (2018) Astrocytic atrophy following status epilepticus parallels reduced Ca2+ activity and impaired synaptic plasticity in the rat hippocampus, Front. Mol. Neurosci., 11, 215, https://doi.org/10.3389/fnmol.2018.00215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kryukov, K. A., Kim, K. K., Magazanik, L. G., and Zaitsev, A. V. (2016) Status epilepticus alters hippocampal long-term synaptic potentiation in a rat lithium-pilocarpine model, NeuroReport, 27, 1191-1195, https://doi.org/10.1097/WNR.0000000000000656.

    Article  CAS  PubMed  Google Scholar 

  21. Clarkson, C., Smeal, R. M., Hasenoehrl, M. G., White, J. A., Rubio, M. E., and Wilcox, K. S. (2020) Ultrastructural and functional changes at the tripartite synapse during epileptogenesis in a model of temporal lobe epilepsy, Exp. Neurol., 326, 113196, https://doi.org/10.1016/j.expneurol.2020.113196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Naylor, D. E., Liu, H., Niquet, J., and Wasterlain, C. G. (2013) Rapid surface accumulation of NMDA receptors increases glutamatergic excitation during status epilepticus, Neurobiol. Dis., 54, 225-238, https://doi.org/10.1016/j.nbd.2012.12.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Amakhin, D. V., Soboleva, E. B., Ergina, J. L., Malkin, S. L., Chizhov, A. V., and Zaitsev, A. V. (2018) Seizure-induced potentiation of AMPA receptor-mediated synaptic transmission in the entorhinal cortex, Front. Cell. Neurosci., 12, 486, https://doi.org/10.3389/fncel.2018.00486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rajasekaran, K., Todorovic, M., and Kapur, J. (2012) Calcium-permeable AMPA receptors are expressed in a rodent model of status epilepticus, Ann. Neurol., 72, 91-102, https://doi.org/10.1002/ana.23570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Amakhin, D. V., Malkin, S. L., Ergina, J. L., Kryukov, K. A., Veniaminova, E. A., Zubareva, O. E., and Zaitsev, A. V. (2017) Alterations in properties of glutamatergic transmission in the temporal cortex and hippocampus following pilocarpine-induced acute seizures in wistar rats, Front. Cell. Neurosci., 11, 264, https://doi.org/10.3389/fncel.2017.00264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Malkin, S. L., Amakhin, D. V., Veniaminova, E. A., Kim, K. K., Zubareva, O. E., Magazanik, L. G., and Zaitsev, A. V. (2016) Changes of AMPA receptor properties in the neocortex and hippocampus following pilocarpine-induced status epilepticus in rats, Neuroscience, 327, 146-155, https://doi.org/10.1016/j.neuroscience.2016.04.024.

    Article  CAS  PubMed  Google Scholar 

  27. Zubareva, O. E., Kovalenko, A. A., Kalemenev, S. V., Schwarz, A. P., Karyakin, V. B., and Zaitsev, A. V. (2018) Alterations in mRNA expression of glutamate receptor subunits and excitatory amino acid transporters following pilocarpine-induced seizures in rats, Neurosci. Lett., 686, 94-100, https://doi.org/10.1016/j.neulet.2018.08.047.

    Article  CAS  PubMed  Google Scholar 

  28. Racine, R. J. (1972) Modification of seizure activity by electrical stimulation. II. Motor seizure, Electroencephalogr. Clin. Neurophysiol., 32, 281-294, https://doi.org/10.1016/0013-4694(72)90177-0.

    Article  CAS  PubMed  Google Scholar 

  29. Postnikova, T. Y., Amakhin, D. V., Trofimova, A. M., Smolensky, I. V., and Zaitsev, A. V. (2019) Changes in functional properties of rat hippocampal neurons following pentylenetetrazole-induced status epilepticus, Neuroscience, 399, 103-116, https://doi.org/10.1016/j.neuroscience.2018.12.029.

    Article  CAS  PubMed  Google Scholar 

  30. Schwarz, A. P., Malygina, D. A., Kovalenko, A. A., Trofimov, A. N., and Zaitsev, A. V. (2020) Multiplex qPCR assay for assessment of reference gene expression stability in rat tissues/samples, Mol. Cell. Probes, 53, 101611, https://doi.org/10.1016/j.mcp.2020.101611.

    Article  CAS  PubMed  Google Scholar 

  31. Livak, K. J., and Schmittgen, T. D. (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method, Methods, 25, 402-428, https://doi.org/10.1006/meth.2001.1262.

    Article  CAS  PubMed  Google Scholar 

  32. Bonefeld, B. E., Elfving, B., and Wegener, G. (2008) Reference genes for normalization: a study of rat brain tissue, Synapse, 62, 302-309, https://doi.org/10.1002/syn.20496.

    Article  CAS  PubMed  Google Scholar 

  33. Lin, W., Burks, C. A., Hansen, D. R., Kinnamon, S. C., and Gilbertson, T. A. (2004) Taste receptor cells express pH-sensitive leak K+ channels, J. Neurophysiol., 92, 2909-2919, https://doi.org/10.1152/jn.01198.2003.

    Article  CAS  PubMed  Google Scholar 

  34. Yamaguchi, M., Yamauchi, A., Nishimura, M., Ueda, N., and Naito, S. (2005) Soybean oil fat emulsion prevents cytochrome P450 mRNA down-regulation induced by fat-free overdose total parenteral nutrition in infant rats, Biol. Pharm. Bull., 28, 143-147, https://doi.org/10.1248/bpb.28.143.

    Article  CAS  PubMed  Google Scholar 

  35. Swijsen, A., Nelissen, K., Janssen, D., Rigo, J. M., and Hoogland, G. (2012) Validation of reference genes for quantitative real-time PCR studies in the dentate gyrus after experimental febrile seizures, BMC Res. Notes, 5, 685, https://doi.org/10.1186/1756-0500-5-685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pohjanvirta, R., Niittynen, M., Lindén, J., Boutros, P. C., Moffat, I. D., and Okey, A. B. (2006) Evaluation of various housekeeping genes for their applicability for normalization of mRNA expression in dioxin-treated rats, Chem. Biol. Interact., 160, 134-149, https://doi.org/10.1016/j.cbi.2006.01.001.

    Article  CAS  PubMed  Google Scholar 

  37. Cook, N. L., Vink, R., Donkin, J. J., and van den Heuvel, C. (2009) Validation of reference genes for normalization of real-time quantitative RT-PCR data in traumatic brain injury, J. Neurosci. Res., 87, 34-41, https://doi.org/10.1002/jnr.21846.

    Article  CAS  PubMed  Google Scholar 

  38. Langnaese, K., John, R., Schweizer, H., Ebmeyer, U., and Keilhoff, G. (2008) Selection of reference genes for quantitative real-time PCR in a rat asphyxial cardiac arrest model, BMC Mol. Biol., 9, 53, https://doi.org/10.1186/1471-2199-9-53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Proudnikov, D., Yuferov, V., Zhou, Y., LaForge, K. S., Ho, A., and Kreek, M. J. (2003) Optimizing primer–probe design for fluorescent PCR, J. Neurosci. Methods, 123, 31-45, https://doi.org/10.1016/S0165-0270(02)00325-4.

    Article  CAS  PubMed  Google Scholar 

  40. Zucker, R. S., and Regehr, W. G. (2002) Short-term synaptic plasticity, Annu. Rev. Physiol., 64, 355-405, https://doi.org/10.1146/annurev.physiol.64.092501.114547.

    Article  CAS  PubMed  Google Scholar 

  41. Owen, B., Bichler, E., and Benveniste, M. (2021) Excitatory synaptic transmission in hippocampal area CA1 is enhanced then reduced as chronic epilepsy progresses, Neurobiol. Dis., 154, 105343, https://doi.org/10.1016/j.nbd.2021.105343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cull-Candy, S. G., and Farrant, M. (2021) Ca2+-permeable AMPA receptors and their auxiliary subunits in synaptic plasticity and disease, J. Physiol., 599, 2655-2671, https://doi.org/10.1113/jp279029.

    Article  CAS  PubMed  Google Scholar 

  43. Andre, V., Marescaux, C., Nehlig, A., and Fritschy, J. M. (2001) Alterations of hippocampal GABAergic system contribute to development of spontaneous recurrent seizures in the at lithium-pilocarpine model of temporal lobe epilepsy, Hippocampus, 11, 452-468, https://doi.org/10.1002/hipo.1060.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Russian Science Foundation (project no. 22-75-00131).

Author information

Authors and Affiliations

  1. Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223, St. Petersburg, Russia

    Georgy P. Diespirov, Tatyana Y. Postnikova, Alexandra V. Griflyuk, Anna A. Kovalenko & Aleksey V. Zaitsev

Authors
  1. Georgy P. Diespirov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tatyana Y. Postnikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexandra V. Griflyuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna A. Kovalenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aleksey V. Zaitsev
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.Y.P., A.V.Z. – study concept and study management; T.Y.P., G.P.D., A.A.K., A.V.G. – experiments; T.Y.P., A.A.K. – analysis of results and statistical processing of data; G.P.D., A.V.G., and A.A.K. – writing of the draft; T.Y.P. and A.V.Z. – editing the article.

Corresponding author

Correspondence to Aleksey V. Zaitsev.

Ethics declarations

The authors declare no conflict of interest. All studies were conducted in accordance with the guidelines for the treatment of laboratory animals approved by the Sechenov Institute of Evolutionary Physiology and Biochemistry Ethics Committee and fully compliant with the international regulations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Diespirov, G.P., Postnikova, T.Y., Griflyuk, A.V. et al. Alterations in the Properties of the Rat Hippocampus Glutamatergic System in the Lithium-Pilocarpine Model of Temporal Lobe Epilepsy. Biochemistry Moscow 88, 353–363 (2023). https://doi.org/10.1134/S0006297923030057

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297923030057

Keywords

Search

Navigation