Skip to main content
NCBI home page
Neuroscience Bulletin logoLink to Neuroscience Bulletin
. 2013 Apr 2;29(5):565–575. doi: 10.1007/s12264-013-1326-y

BDNF-TrkB signaling pathway is involved in pentylenetetrazoleevoked progression of epileptiform activity in hippocampal neurons in anesthetized rats

Xu Liu 1, Jia Liu 1, Juan Liu 1, Xiao-Ling Liu 2, Ling-Yan Jin 2, Wei Fan 1, Jin Ding 1, Li-Chao Peng 2, Yun Wang 1,✉, Xin Wang 1,✉
PMCID: PMC5561949  PMID: 23550026

Abstract

Pentylenetetrazole (PTZ) is a widely-used convulsant used in studies of epilepsy; its subcutaneous injection generates an animal model with stable seizures. Here, we compared the ability of PTZ via the intravenous and subcutaneous routes to evoke progressive epileptiform activity in the hippocampal CA1 neurons of anesthetized rats. The involvement of the BDNF-TrkB pathway was then investigated. When PTZ was given intravenously, it induced epileptiform bursting activity at a short latency in a dose-dependent manner. However, when PTZ was given subcutaneously, it induced a slowly-developing pattern of epileptogenesis; first, generating multiple population-spike peaks, then spontaneous interictal discharge-like spike, leading to the final ictal discharge-like, highly synchronized bursting fi ring in the CA1 pyramidal layer of the hippocampus. K252a, a TrkB receptor antagonist, when given by intracerebroventricular injection, signifi cantly reduced the probability of multiple population spike peaks induced by subcutaneous injection of PTZ, delayed the latency of spontaneous spikes, and reduced the burst frequency. Our results indicate that PTZ induces a progressive change of neuronal epileptiform activity in the hippocampus, and the BDNF-TrkB signaling pathway is mainly involved in the early phases of epileptogenesis, but not the synchronized neuronal burst activity associated with epileptic seizure in the PTZ animal model. These results provide basic insights into the changing pattern of hippocampal neuronal activity during the development of the PTZ seizure model, and establish an in vivo seizure model useful for future electrophysiological studies of epilepsy.

Keywords: epilepsy, pentamethylenetetrazole, hippocampus, BDNF, TrkB

Contributor Information

Yun Wang, Email: yunwang@fudan.edu.cn.

Xin Wang, Email: wang.xin@zs-hospital.sh.cn.

References

  • [1].Qu H, Eloqayli H, Sonnewald U. Pentylenetetrazole affects metabolism of astrocytes in culture. J Neurosci Res. 2005;79:48–54. doi: 10.1002/jnr.20306. [DOI] [PubMed] [Google Scholar]
  • [2].Zhao R, Weng CC, Feng Q, Chen L, Zhang XY, Zhu HY, et al. Anticonvulsant activity of BmK AS, a sodium channel site 4-specific modulator. Epilepsy Behav. 2011;20:267–276. doi: 10.1016/j.yebeh.2010.12.006. [DOI] [PubMed] [Google Scholar]
  • [3].Qian B, Sun Y, Wu Z, Wan L, Chen L, Kong S, et al. Epileptiform response of CA1 neurones to convulsant stimulation by cyclothiazide, kainic acid and pentylenetetrazol in anaesthetised rats. Seizure. 2011;20:312–319. doi: 10.1016/j.seizure.2010.12.016. [DOI] [PubMed] [Google Scholar]
  • [4].Barde YA, Edgar D, Thoenen H. Purification of a new neurotrophic factor from mammalian brain. EMBO J. 1982;1(5):549–553. doi: 10.1002/j.1460-2075.1982.tb01207.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [5].Binder DK. Neurotrophins in the dentate gyrus. Prog Brain Res. 2007;163:371–397. doi: 10.1016/S0079-6123(07)63022-2. [DOI] [PubMed] [Google Scholar]
  • [6].Cardile V, Pavone A, Gulino R, Renis M, Scifo C, Perciavalle V. Expression of brain-derived neurotrophic factor (BDNF) and inducible nitric oxide synthase (iNOS) in rat astrocyte cultures treated with Levetiracetam. Brain Res. 2003;976:227–233. doi: 10.1016/S0006-8993(03)02720-3. [DOI] [PubMed] [Google Scholar]
  • [7].Goodman LJ, Valverde J, Lim F, Geschwind MD, Federoff HJ, Geller AI, et al. Regulated release and polarized localization of brain-derived neurotrophic factor in hippocampal neurons. Mol Cell Neurosci. 1996;7:222–238. doi: 10.1006/mcne.1996.0017. [DOI] [PubMed] [Google Scholar]
  • [8].Balkowiec A, Katz DM. Activity-dependent release of endogenous brain-derived neurotrophic factor from primary sensory neurons detected by ELISA in situ. J Neurosci. 2000;20:7417–7423. doi: 10.1523/JNEUROSCI.20-19-07417.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [9].Binder DK, Croll SD, Gall CM, Scharfman HE. BDNF and epilepsy: too much of a good thing? Trends Neurosci. 2001;24:47–53. doi: 10.1016/S0166-2236(00)01682-9. [DOI] [PubMed] [Google Scholar]
  • [10].Croll SD, Suri C, Compton DL, Simmons MV, Yancopoulos GD, Lindsay RM, et al. Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex. Neuroscience. 1999;93(4):1491–1506. doi: 10.1016/S0306-4522(99)00296-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [11].Papaleo F, Silverman JL, Aney J, Tian Q, Barkan CL, Chadman KK, et al. Working memory deficits, increased anxiety-like traits, and seizure susceptibility in BDNF overexpressing mice. Learn Mem. 2011;18(8):534–544. doi: 10.1101/lm.2213711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [12].Kotloski R, McNamara JO. Reduction of TrkB expression de novo in the adult mouse impairs epileptogenesis in the kindling model. Hippocampus. 2010;20(6):713–723. doi: 10.1002/hipo.20673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].Kafitz KW, Rose CR, Thoenen H, Konnerth A. Neurotrophinevoked rapid excitation through TrkB receptors. Nature. 1999;401:918–921. doi: 10.1038/44847. [DOI] [PubMed] [Google Scholar]
  • [14].Rose CR, Blum R, Kafitz KW, Kovalchuk Y, Konnerth A. From modulator to mediator: rapid effects of BDNF on ion channels. Bioessays. 2004;26:1185–1194. doi: 10.1002/bies.20118. [DOI] [PubMed] [Google Scholar]
  • [15].Gall C, Lauterborn J, Bundman M, Murray K, Isackson P. Seizures and the regulation of neurotrophic factor and neuropeptide gene expression in brain. Epilepsy Res Suppl. 1991;4:225–245. [PubMed] [Google Scholar]
  • [16].Elmer E, Kokaia Z, Kokaia M, Carnahan J, Nawa H, Lindvall O. Dynamic changes of brain-derived neurotrophic factor protein levels in the rat forebrain after single and recurring kindling-induced seizures. Neuroscience. 1998;83:351–362. doi: 10.1016/S0306-4522(97)00387-4. [DOI] [PubMed] [Google Scholar]
  • [17].He XP, Minichiello L, Klein R, McNamara JO. Immunohistochemical evidence of seizure-induced activation of trkB receptors in the mossy fiber pathway of adult mouse hippocampus. J Neurosci. 2002;22:7502–7508. doi: 10.1523/JNEUROSCI.22-17-07502.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [18].Kokaia M, Ernfors P, Kokaia Z, Elmér E, Jaenisch R, Lindvall O. Suppressed epileptogenesis in BDNF mutant mice. Exp Neurol. 1995;133:215–224. doi: 10.1006/exnr.1995.1024. [DOI] [PubMed] [Google Scholar]
  • [19].Bergami M, Berninger B, Canossa M. Conditional deletion of TrkB alters adult hippocampal neurogenesis and anxietyrelated behavior. Commun Integr Biol. 2009;2:14–16. doi: 10.4161/cib.2.1.7349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [20].Wang Y, Qi JS, Kong S, Sun Y, Fan J, Jiang M, et al. BDNFTrkB signaling pathway mediates the induction of epileptiform activity induced by a convulsant drug cyclothiazide. Neuropharmacology. 2009;57:49–59. doi: 10.1016/j.neuropharm.2009.04.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [21].Scharfman HE, Goodman JH, Sollas AL, Croll SD. Spontaneous limbic seizures after intrahippocampal infusion of brain-derived neurotrophic factor. Exp Neurol. 2002;174:201–214. doi: 10.1006/exnr.2002.7869. [DOI] [PubMed] [Google Scholar]
  • [22].Lahteinen S, Pitkanen A, Saarelainen T, Nissinen J, Koponen E, Castrén E. Decreased BDNF signaling in transgenic mice reduces epileptogenesis. Eur J Neurosci. 2002;15:721–734. doi: 10.1046/j.1460-9568.2002.01897.x. [DOI] [PubMed] [Google Scholar]
  • [23].Gleeson LC, Ryan KJ, Griffin EW, Connor TJ, Harkin A. The beta2-adrenoceptor agonist clenbuterol elicits neuroprotective, anti-inflammatory and neurotrophic actions in the kainic acid model of excitotoxicity. Brain Behav Immun. 2010;24:1354–1361. doi: 10.1016/j.bbi.2010.06.015. [DOI] [PubMed] [Google Scholar]
  • [24].Paradiso B, Zucchini S, Su T, Bovolenta R, Berto E, Marconi P, et al. Localized overexpression of FGF-2 and BDNF in hippocampus reduces mossy fiber sprouting and spontaneous seizures up to 4 weeks after pilocarpineinduced status epilepticus. Epilepsia. 2011;52:572–578. doi: 10.1111/j.1528-1167.2010.02930.x. [DOI] [PubMed] [Google Scholar]
  • [25].Tongiorgi E, Armellin M, Giulianini PG, Bregola G, Zucchini S, Paradiso B, et al. Brain-derived neurotrophic factor mRNA and protein are targeted to discrete dendritic laminas by events that trigger epileptogenesis. J Neurosci. 2004;24:6842–6852. doi: 10.1523/JNEUROSCI.5471-03.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Nanda SA, Mack KJ. Seizures and sensory stimulation result in different patterns of brain derived neurotrophic factor protein expression in the barrel cortex and hippocampus. Brain Res Mol Brain Res. 2000;78:1–14. doi: 10.1016/S0169-328X(00)00054-1. [DOI] [PubMed] [Google Scholar]
  • [27].Zhu H, Chen MF, Yu WJ, Wang WJ, Li F, Liu W T, et al. ime-dependent changes in BDNF expression of pentylenetetrazole-induced hippocampal astrocytes in vitro. Brain Res. 2012;1439:1–6. doi: 10.1016/j.brainres.2011.12.035. [DOI] [PubMed] [Google Scholar]
  • [28].Behr J, Lyson KJ, Mody I. Enhanced propagation of epileptiform activity through the kindled dentate gyrus. J Neurophysiol. 1998;79(4):1726–1732. doi: 10.1152/jn.1998.79.4.1726. [DOI] [PubMed] [Google Scholar]
  • [29].Kong S, Qian B, Liu J, Fan M, Chen G, Wang Y. Cyclothiazide induces seizure behavior in freely moving rats. Brain Res. 2010;1355:207–213. doi: 10.1016/j.brainres.2010.07.088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [30].Qi J, Wang Y, Jiang M, Warren P, Chen G. Cyclothiazide induces robust epileptiform activity in rat hippocampal neurons both in vitro and in vivo. J Physiol. 2006;571:605–618. doi: 10.1113/jphysiol.2005.103812. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [31].Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates, seconded. New York: Academic Press; 1986. [Google Scholar]
  • [32].Wheal HV, Bernard C, Chad JE, Cannon RC. Pro-epileptic changes in synaptic function can be accompanied by proepileptic changes in neuronal excitability. Trends Neurosci. 1998;21:167–174. doi: 10.1016/S0166-2236(97)01182-X. [DOI] [PubMed] [Google Scholar]
  • [33].Pavlova T, Stepanichev M, Gulyaeva N. Pentylenetetrazole kindling induces neuronal cyclin B1 expression in rat hippocampus. Neurosci Lett. 2006;392:154–158. doi: 10.1016/j.neulet.2005.09.021. [DOI] [PubMed] [Google Scholar]
  • [34].Jiang W, Xiao L, Wang JC, Huang YG, Zhang X. Effects of nitric oxide on dentate gyrus cell proliferation after seizures induced by pentylenetrazol in the adult rat brain. Neurosci Lett. 2004;367:344–348. doi: 10.1016/j.neulet.2004.06.031. [DOI] [PubMed] [Google Scholar]
  • [35].Meilleur S, Aznavour N, Descarries L, Carmant L, Mamer OA, Psarropoulou C. Pentylenetetrazol-induced seizures in immature rats provoke long-term changes in adult hippocampal cholinergic excitability. Epilepsia. 2003;44:507–517. doi: 10.1046/j.1528-1157.2003.44402.x. [DOI] [PubMed] [Google Scholar]
  • [36].Raza M, Shaheen F, Choudhary MI, Rahman AU, Sombati S, DeLorenzo RJ. In vitro inhibition of pentylenetetrazole and bicuculline-induced epileptiform activity in rat hippocampal pyramidal neurons by aqueous fraction isolated from Delphinium denudatum. Neurosci Lett. 2002;333:103–106. doi: 10.1016/S0304-3940(02)01027-3. [DOI] [PubMed] [Google Scholar]
  • [37].Avoli M, D’Antuono M, Louvel J, Köhling R, Biagini G, Pumain R, et al. Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro. Prog Neurobiol. 2002;68:167–207. doi: 10.1016/S0301-0082(02)00077-1. [DOI] [PubMed] [Google Scholar]
  • [38].Avoli M, Louvel J, Pumain R, Köhling R. Cellular and molecular mechanisms of epilepsy in the human brain. Prog Neurobiol. 2005;77:166–200. doi: 10.1016/j.pneurobio.2005.09.006. [DOI] [PubMed] [Google Scholar]
  • [39].Binder DK, Scharfman HE. Brain-derived neurotrophic factor. Growth Factors. 2004;22:123–131. doi: 10.1080/08977190410001723308. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [40].Jones KR, Reichardt LF. Molecular cloning of a human gene that is a member of the nerve growth factor family. Proc Natl Acad Sci U S A. 1990;87:8060–8064. doi: 10.1073/pnas.87.20.8060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [41].Maisonpierre PC, Le BMM, Espinosa R, 3rd, Ip NY, Belluscio L, de la Monte SM, et al. Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations. Genomics. 1991;10:558–568. doi: 10.1016/0888-7543(91)90436-I. [DOI] [PubMed] [Google Scholar]
  • [42].Acheson A, Conover JC, Fandl JP, DeChiara TM, Russell M, Thadani A, et al. A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature. 1995;374:450–453. doi: 10.1038/374450a0. [DOI] [PubMed] [Google Scholar]
  • [43].Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci. 2001;24:677–736. doi: 10.1146/annurev.neuro.24.1.677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [44].Yamada K, Nabeshima T. Brain-derived neurotrophic factor/ TrkB signaling in memory processes. J Pharmacol Sci. 2003;91:267–270. doi: 10.1254/jphs.91.267. [DOI] [PubMed] [Google Scholar]
  • [45].Lee MC, Okamoto M, Liu YF, Inoue K, Matsui T, Nogami H, et al. Voluntary resistance running with short distance enhances spatial memory related to hippocampal BDNF signaling. J Appl Physiol. 2012;113(8):1260–1266. doi: 10.1152/japplphysiol.00869.2012. [DOI] [PubMed] [Google Scholar]
  • [46].Patapoutian A, Reichardt LF. Trk receptors: mediators of neurotrophin action. Curr Opin Neurobiol. 2001;11:272–280. doi: 10.1016/S0959-4388(00)00208-7. [DOI] [PubMed] [Google Scholar]
  • [47].Kang H, Schuman EM. Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science. 1995;267:1658–1662. doi: 10.1126/science.7886457. [DOI] [PubMed] [Google Scholar]
  • [48].Zhu WJ, Roper SN. Brain-derived neurotrophic factor enhances fast excitatory synaptic transmission in human epileptic dentate gyrus. Ann Neurol. 2001;50:188–194. doi: 10.1002/ana.1074. [DOI] [PubMed] [Google Scholar]

Articles from Neuroscience Bulletin are provided here courtesy of Springer

RESOURCES