, Volume 49, Issue 1, pp 8–18 | Cite as

Hypothermic Suppression of Epileptiform Bursting Activity of a Hyppocampal Granule Neuron Possessing Thermosensitive TRP Channels (a Model Study: Biophysical and Clinical Aspects)

  • L. E. Demianenko
  • E. P. Poddubnaya
  • I. A. Makedonsky
  • I. B. Kulagina
  • S. M. Korogod

Synchronous burst discharges of action potentials (APs) of neurons are typical manifestations of cerebral epileptiform activity; such discharges are reflected in EEG as burst-suppression episodes. For elimination of drug-resistant epileptogenic foci, therapeutic hypothermia (controlled decrease in the body temperature) is increasingly used; at the same time, the mechanisms of its therapeutic effect remain largely unknown. We investigated one of the respective possible mechanisms on a model of the granule neuron (GN) of the hippocampal dentate gyrus. These cells are the first links in three-synaptic neuronal chains of the hippocampus; the latter is the brain region where sources of epileptiform activity are often localized. In the somatodendritic membrane of the GN model, thermosensitive channels of the TRP family, which conduct a depolarizing current, were included along with other ion channels inherent in these neurons. It has been found that such channels are indeed expressed in GNs. In response to tonic synaptic excitation uniformly distributed over the dendrites, the GN at 37°C (normothermia) generated periodic multipulse burst discharges. Lowering the temperature to 36, 34, 32, and 30°C (borders of weak, moderate, moderately deep, and deep therapeutic hypothermia, respectively) led to degradation of the bursting patterns and their transformation into low-frequency trains of separate APs. Precisely at these temperatures, is the depolarizing current through TRP channels deactivated. The phenomenon of degradation of bursting activity generated by the model GN corresponded to a multifold decrease in the amplitude, duration, and repetition frequency of the burst-suppression episodes in EEGs of newborn infants suffering from hypoxic-ischemic CNS injury, which we observed in clinics under conditions of moderate hypothermia (34°C) used for treatment of such patients. These observations allow us to suggest that hypothermic suppression of bursting discharges of hippocampal neurons possessing thermosensitive TRP channels may be one of the mechanisms of the therapeutic effect of hypothermia.


granule neuron (GN) dentate gyrus hippocampus TRP channels temperature sensitivity excitability epileptiform EEG therapeutic hypothermia computer models 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    D. A. McCormick and D. Contreras, “On the cellular and network bases of epileptic seizures,” Annu. Rev. Physiol., 63, 815-846 (2001).CrossRefPubMedGoogle Scholar
  2. 2.
    R. K. S. Wong, R. Miles, and R. D. Traub, “Local circuit interactions in synchronization of cortical neurones,” J. Exp. Biol., 112, No. 1, 169-178 (1984).PubMedGoogle Scholar
  3. 3.
    R. D. Traub, J. G. R. Jefferys, R. Miles, et al., “A branching dendritic model of a rodent CA3 pyramidal neurone,” J. Physiol., 481, Part 1, 79-95 (1994).CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    D. Amaral and P. Lavenex, «Hippocampal neuroanatomy,» in: The Hippocampus Book, P. Andersen, R. Morris, D. Amaral, et al. (eds.), Oxford Univ. Press, Oxford, 37-115 (2006).Google Scholar
  5. 5.
    A. Hazra, R. Rosenbaum, B. Bodmann, et al., “β-Adrenergic modulation of spontaneous spatiotemporal activity patterns and synchrony in hyperexcitable hippocampal circuits,” J. Neurophysiol., 108, No. 2, 658-671 (2012).CrossRefPubMedGoogle Scholar
  6. 6.
    G. K. Motamedi, R. P. Lesser, and S. Vicini, “Therapeutic brain hypothermia, its mechanisms of action, and its prospects as a treatment for epilepsy,” Epilepsia, 54, No. 6, 959-970 (2013).CrossRefPubMedGoogle Scholar
  7. 7.
    S. M. Korogod and L. E. Demianenko, “Temperature deactivation of depolarizing TRP-current as a mechanism of neuronal activity inhibition during hypothermia,” Neurophysiology, 48 , Nos. 5/6, 406-414 (2016).Google Scholar
  8. 8.
    C. Harteneck and K. Leuner, “TRP channels in neuronal and glial signal transduction,” in: Neurochemistry, T. Heinbockel (ed.), InTech (2014).Google Scholar
  9. 9.
    K. Shibasaki, M. Suzuki, A. Mizuno, and M. Tominaga, “Effects of body temperature on neural activity in the hippocampus: regulation of resting membrane potentials by transient receptor potential vanilloid 4,” J. Neurosci., 27, No. 7, 1566-1575 (2007).CrossRefPubMedGoogle Scholar
  10. 10.
    A. Menigoz, T. Ahmed, V. Sabanov, et al., “TRPM4-dependent post-synaptic depolarization is essential for the induction of NMDA receptor-dependent LTP in CA1 hippocampal neurons,” Pflügers Arch. Eur. J. Physiol., 468, No. 4, 593-607 (2016).CrossRefGoogle Scholar
  11. 11.
    C. Schmidt-Hieber, P. Jonas, and J. Bischofberger, “Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus,” Nature, 429, No. 6988, 184-187 (2004).CrossRefPubMedGoogle Scholar
  12. 12.
    I. Aradi and W. R. Holmes, “Role of multiple calcium and calcium-dependent conductances in regulation of hippocampal dentate granule cell excitability,” J. Comput. Neurosci., 6, No. 3, 215-235 (1999).CrossRefPubMedGoogle Scholar
  13. 13.
    A. Chávez, V. Hernández, A. Rodenas-Ruano, et al., “Compartment-specific modulation of GABAergic synaptic transmission by TRPV1 channels in the dentate gyrus,” J. Neurosci., 34, No. 50, 16621-16629 (2014).CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    N. T. Carnevale and M. L. Hines, The NEURON Book, Cambridge Univ. Press, Cambridge (2006).CrossRefGoogle Scholar
  15. 15.
    C. Schmidt-Hieber, P. Jonas, and J. Bischofberger, “Subthreshold dendritic signal processing and coincidence detection in dentate gyrus granule cells,” J. Neurosci., 27, No. 31, 8430-8441 (2007).CrossRefPubMedGoogle Scholar
  16. 16.
    H. O. Lüders and S. Noachtar, Atlas and Classification of Electroencephalography, W. B. Saunders (ed.), Philadelphia (2000).Google Scholar
  17. 17.
    M. N. Nenov, F. Tempia, L. Denner, et al., “Impaired firing properties of dentate granule neurons in an Alzheimer’s disease animal model are rescued by PPARγ agonism,” J. Neurophysiol., 113, No. 6, 1712-1726 (2015).CrossRefPubMedGoogle Scholar
  18. 18.
    T. L. Babb and P. H. Crandall, “Epileptogenesis of human limbic neurons in psychomotor epileptics,” Electroencephalogr. Clin. Neurophysiol., 40, No. 3, 225-243 (1976).CrossRefPubMedGoogle Scholar
  19. 19.
    M. Steriade, F. Amzica, and D. Contreras, “Cortical and thalamic cellular correlates of electroencephalographic burst-suppression,” Electroencephalogr. Clin. Neurophysiol., 90, No. 1, 1-16 (1994).CrossRefPubMedGoogle Scholar
  20. 20.
    D. Kroeger, B. Florea, and F. Amzica, “Human brain activity patterns beyond the isoelectric line of extreme deep coma,” PLoS One, 8, No. 9, e75257 (2013).CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    M. Steriade, F. Amzica, D. Neckelmann, and I. Timofeev, “Spike-wave complexes and fast components of cortically generated seizures. II. Extra- and intracellular patterns,” J. Neurophysiol., 80, No. 3, 1456-1479 (1998).PubMedGoogle Scholar
  22. 22.
    M.-D. Lamblin, E. W. Esquivel, and M. André, “The electroencephalogram of the full-term newborn: review of normal features and hypoxic-ischemic encephalopathy patterns,” Neurophysiol. Clin., 43, Nos. 5/6, 267-287 (2013).CrossRefPubMedGoogle Scholar
  23. 23.
    S. R. Sinha and P. Saggau, “Imaging of 4-AP-induced, GABA(A)-dependent spontaneous synchronized activity mediated by the hippocampal interneuron network,” J. Neurophysiol., 86, No. 1, 381-391 (2001).PubMedGoogle Scholar
  24. 24.
    S. P. Javedan, R. S. Fisher, H. G. Eder, et al., “Cooling abolishes neuronal network synchronization in rat hippocampal slices,” Epilepsia, 43, No. 6, 574-580 (2002).CrossRefPubMedGoogle Scholar
  25. 25.
    I. B. Kulagina, V. I. Kukushka, and S. M. Korogod, “Structure-dependent electrical and concentration processes in the dendrites of pyramidal neurons of superficial neocortical layers: Model study,” Neurophysiology, 43, No. 2, 77-89 (2011).CrossRefGoogle Scholar
  26. 26.
    L. El-Hassar, A. M. Hagenston, L. B. D’Angelo, and M. F. Yeckel, “Metabotropic glutamate receptors regulate hippocampal CA1 pyramidal neuron excitability via Ca2+ wave-dependent activation of SK and TRPC channels,” J. Physiol., 589, Part 13, 3211-3229 (2011).CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    K. Shibasaki, M. Tominaga, and Y. Ishizaki, “Hippocampal neuronal maturation triggers postsynaptic clustering of brain temperature-sensor TRPV4,” Biochem. Biophys. Res. Commun., 458, No. 1, 168-173 (2015).CrossRefPubMedGoogle Scholar
  28. 28.
    J. Ben-Ari, J.-L. Gaiarsa, R. Tyzio, and R. Khazipov, “GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations,” Physiol. Rev., 87, No. 4, 1215-1284 (2007).CrossRefPubMedGoogle Scholar
  29. 29.
    J. Ben-Ari, M. Woodin, E. Sernagor, et al., “Refuting the challenges of the developmental shift of polarity of GABA actions: GABA more exciting than ever!” Front. Cell. Neurosci., 6, Art. 35, 1-18 (2012).Google Scholar
  30. 30.
    P. Bregestovski and C. Bernard, “Excitatory GABA: How a correct observation may turn out to be an experimental artifact,” Front. Pharmacol., 3, Art. 65, 1-8 (2012).Google Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • L. E. Demianenko
    • 1
  • E. P. Poddubnaya
    • 2
  • I. A. Makedonsky
    • 2
  • I. B. Kulagina
    • 1
  • S. M. Korogod
    • 3
  1. 1.Dnipropetrovsk Medical Academy, Ministry of Public Health of UkraineDniproUkraine
  2. 2.Rudnev Dnipropetrovsk Specialized Clinical Medical Center for Mother and Child, Dnipropetrovsk Regional CouncilDniproUkraine
  3. 3.Bogomolets Institute of Physiology, National Academy of Sciences of UkraineKyivUkraine

Personalised recommendations