Skip to main content
PMC home page
Neuroscience Bulletin logoLink to Neuroscience Bulletin
. 2013 Jan 30;29(1):28–36. doi: 10.1007/s12264-013-1304-4

Spatiotemporal dynamics of high-K+-induced epileptiform discharges in hippocampal slice and the effects of valproate

Jian-Sheng Liu 1, Jing-Bo Li 1, Xin-Wei Gong 2, Hai-Qing Gong 2, Pu-Ming Zhang 2, Pei-Ji Liang 2,✉, Qin-Chi Lu 1,✉
PMCID: PMC5561865  PMID: 23361520

Abstract

The epileptic seizure is a dynamic process involving a rapid transition from normal activity to a state of hypersynchronous neuronal discharges. Here we investigated the network properties of epileptiform discharges in hippocampal slices in the presence of high K+ concentration (8.5 mmol/L) in the bath, and the effects of the anti-epileptic drug valproate (VPA) on epileptiform discharges, using a microelectrode array. We demonstrated that epileptiform discharges were predominantly initiated from the stratum pyramidale layer of CA3a-b and propagated bi-directionally to CA1 and CA3c. Disconnection of CA3 from CA1 abolished the discharges in CA1 without disrupting the initiation of discharges in CA3. Further pharmacological experiments showed that VPA at a clinically relevant concentration (100 μmol/L) suppressed the propagation speed but not the rate or duration of high-K+-induced discharges. Our findings suggest that pacemakers exist in the CA3a-b region for the generation of epileptiform discharges in the hippocampus. VPA reduces the conduction of such discharges in the network by reducing the propagation speed.

Keywords: epileptiform discharges, hippocampal slices, microelectrode array, valproate

Contributor Information

Pei-Ji Liang, Email: pjliang@sjtu.edu.cn.

Qin-Chi Lu, Email: qinchilu2011@yahoo.com.cn.

References

  • [1].Wittner L., Miles R. Factors defining a pacemaker region for synchrony in the hippocampus. J Physiol. 2007;584:867–883. doi: 10.1113/jphysiol.2007.138131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [2].Miles R., Wong R.K. Single neurones can initiate synchronized population discharge in the hippocampus. Nature. 1983;306:371–373. doi: 10.1038/306371a0. [DOI] [PubMed] [Google Scholar]
  • [3].Jensen M.S., Yaari Y. Role of intrinsic burst firing, potassium accumulation, and electrical coupling in the elevated potassium model of hippocampal epilepsy. J Neurophysiol. 1997;77:1224–1233. doi: 10.1152/jn.1997.77.3.1224. [DOI] [PubMed] [Google Scholar]
  • [4].McCormick D.A., Contreras D. On the cellular and network bases of epileptic seizures. Annu Rev Physiol. 2001;63:815–846. doi: 10.1146/annurev.physiol.63.1.815. [DOI] [PubMed] [Google Scholar]
  • [5].Ermentrout B. The analysis of synaptically generated traveling waves. J Comput Neurosci. 1998;5:191–208. doi: 10.1023/A:1008822117809. [DOI] [PubMed] [Google Scholar]
  • [6].Wu J.Y., Guan L., Tsau Y. Propagating activation during oscillations and evoked responses in neocortical slices. J Neurosci. 1999;19:5005–5015. doi: 10.1523/JNEUROSCI.19-12-05005.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [7].Golomb D., Amitai Y. Propagating neuronal discharges in neocortical slices: computational and experimental study. J Neurophysiol. 1997;78:1199–1211. doi: 10.1152/jn.1997.78.3.1199. [DOI] [PubMed] [Google Scholar]
  • [8].Trevelyan A.J., Sussillo D., Yuste R. Feedforward inhibition contributes to the control of epilepti form propagation speed. J Neurosci. 2007;27:3383–3387. doi: 10.1523/JNEUROSCI.0145-07.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [9].Telfeian A.E., Connors B.W. Epileptiform propagation patterns mediated by NMDA and non-NMDA receptors in rat neocortex. Epilepsia. 1999;40:1499–1506. doi: 10.1111/j.1528-1157.1999.tb02032.x. [DOI] [PubMed] [Google Scholar]
  • [10].Dzhala V.I., Staley K.J. Transition from interictal to ictal activity in limbic networks in vitro. J Neurosci. 2003;23:7873–7880. doi: 10.1523/JNEUROSCI.23-21-07873.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [11].Goda M., Kovac S., Speckmann E.J., Gorji A. Glutamate and dopamine receptors contribute to the lateral spread of epileptiform discharges in rat neocortical slices. Epilepsia. 2008;49:237–247. doi: 10.1111/j.1528-1167.2007.01385.x. [DOI] [PubMed] [Google Scholar]
  • [12].Hill A.J., Jones N.A., Williams C.M., Stephens G.J., Whalley B.J. Development of multi-electrode array screening for anticonvulsants in acute rat brain slices. J Neurosci Methods. 2010;185:246–256. doi: 10.1016/j.jneumeth.2009.10.007. [DOI] [PubMed] [Google Scholar]
  • [13].Liu J.S., Gong X.W., Gong H.Q., Zhang P.M., Liang P.J., Lu Q.C. Exploring spatiotemporal patterns of epileptiform discharge in hippocampal slice using multi-electrode arrays. Acta physiol Sin. 2010;62:163–170. [PubMed] [Google Scholar]
  • [14].Paxinos G. The Rat Nervous System. San Diego: Elsevier Academic Press; 2004. [Google Scholar]
  • [15].de la Prida L.M., Huberfeld G., Cohen I., Miles R. Threshold behavior in the initiation of hippocampal population bursts. Neuron. 2006;49:131–142. doi: 10.1016/j.neuron.2005.10.034. [DOI] [PubMed] [Google Scholar]
  • [16].Gong X.W., Yang F., Liu J.S., Lu Q.C., Gong H.Q., Liang P.J., et al. Investigation of the initiation site and propagation of epileptiform discharges in hippocampal slices using microelectrode array. Prog Biochem Biophys. 2010;37:1240–1247. doi: 10.3724/SP.J.1206.2010.00065. [DOI] [Google Scholar]
  • [17].Johannessen C.U., Johannessen S.I. Valproate: past, present, and future. CNS Drug Rev. 2003;9:199–216. doi: 10.1111/j.1527-3458.2003.tb00249.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [18].Novak J.L., Wheeler B.C. Two-dimensional current source density analysis of propagation delays for components of epileptiform bursts in rat hippocampal slices. Brain Res. 1989;497:223–230. doi: 10.1016/0006-8993(89)90266-7. [DOI] [PubMed] [Google Scholar]
  • [19].Wheeler B.C., Novak J.L. Current source density estimation using microelectrode array data from the hippocampal slice preparation. IEEE Trans Biomed Eng. 1986;33:1204–1212. doi: 10.1109/TBME.1986.325701. [DOI] [PubMed] [Google Scholar]
  • [20].Yang F., Gong X., Gong H., Zhang P., Liang P., Lu Q. Microelectrode array recordings of excitability of low Mg2+-induced acute hippocampal slices. Neural Regen Res. 2010;5:1548–1551. [Google Scholar]
  • [21].Isaeva E., Isaev D., Khazipov R., Holmes G.L. Selective impairment of GABAergic synaptic transmission in the flurothyl model of neonatal seizures. Eur J Neurosci. 2006;23:1559–1566. doi: 10.1111/j.1460-9568.2006.04693.x. [DOI] [PubMed] [Google Scholar]
  • [22].Debanne D., Thompson S.M., Gahwiler B.H. A brief period of epileptiform activity strengthens excitatory synapses in the rat hippocampus in vitro. Epilepsia. 2006;47:247–256. doi: 10.1111/j.1528-1167.2006.00416.x. [DOI] [PubMed] [Google Scholar]
  • [23].Avoli M., D’Antuono M., Louvel J., Kohling 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]
  • [24].Cohen I., Miles R. Contributions of intrinsic and synaptic activities to the generation of neuronal discharges in in vitro hippocampus. J Physiol. 2000;524Pt2:485–502. doi: 10.1111/j.1469-7793.2000.00485.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [25].Bains J.S., Longacher J.M., Staley K.J. Reciprocal interactions between CA3 network activity and strength of recurrent collateral synapses. Nat Neurosci. 1999;2:720–726. doi: 10.1038/11184. [DOI] [PubMed] [Google Scholar]
  • [26].Colom L.V., Saggau P. Spontaneous interictal-like activity originates in multiple areas of the CA2-CA3 region of hippocampal slices. J Neurophysiol. 1994;71:1574–1585. doi: 10.1152/jn.1994.71.4.1574. [DOI] [PubMed] [Google Scholar]
  • [27].Barbarosie M., Avoli M. CA3-driven hippocampal-entorhinal loop controls rather than sustains in vitro limbic seizures. J Neurosci. 1997;17:9308–9314. doi: 10.1523/JNEUROSCI.17-23-09308.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [28].Cohen I., Navarro V., Clemenceau S., Baulac M., Miles R. On the origin of interictal activity in human temporal lobe epilepsy in vitro. Science. 2002;298:1418–1421. doi: 10.1126/science.1076510. [DOI] [PubMed] [Google Scholar]
  • [29].Derchansky M., Rokni D., Rick J.T., Wennberg R., Bardakjian B.L., Zhang L., et al. Bidirectional multisite seizure propagation in the intact isolated hippocampus: the multifocality of the seizure “focus”. Neurobiol Dis. 2006;23:312–328. doi: 10.1016/j.nbd.2006.03.014. [DOI] [PubMed] [Google Scholar]
  • [30].Weissinger F., Buchheim K., Siegmund H., Heinemann U., Meierkord H. Optical imaging reveals characteristic seizure onsets, spread patterns, and propagation velocities in hippocampal-entorhinal cortex slices of juvenile rats. Neurobiol Dis. 2000;7:286–298. doi: 10.1006/nbdi.2000.0298. [DOI] [PubMed] [Google Scholar]
  • [31].Taube J.S., Schwartzkroin P.A. Mechanisms of long-term potentiation: EPSP/spike dissociation, intradendritic recordings, and glutamate sensitivity. J Neurosci. 1988;8:1632–1644. doi: 10.1523/JNEUROSCI.08-05-01632.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [32].Baude A., Nusser Z., Molnar E., McIlhinney R.A., Somogyi P. High-resolution immunogold localization of AMPA type glutamate receptor subunits at synaptic and non-synaptic sites in rat hippocampus. Neuroscience. 1995;69:1031–1055. doi: 10.1016/0306-4522(95)00350-R. [DOI] [PubMed] [Google Scholar]
  • [33].Bruckner C., Stenkamp K., Meierkord H., Heinemann U. Epileptiform discharges induced by combined application of bicuculline and 4-aminopyridine are resistant to standard anticonvulsants in slices of rats. Neurosci Lett. 1999;268:163–165. doi: 10.1016/S0304-3940(99)00341-9. [DOI] [PubMed] [Google Scholar]
  • [34].D’Antuono M., Kohling R., Ricalzone S., Gotman J., Biagini G., Avoli M. Antiepileptic drugs abolish ictal but not interictal epileptiform discharges in vitro. Epilepsia. 2010;51:423–431. doi: 10.1111/j.1528-1167.2009.02273.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [35].Spencer S.S., Goncharova I.I., Duckrow R.B., Novotny E.J., Zaveri H.P. Interictal spikes on intracranial recording: behavior, physiology, and implications. Epilepsia. 2008;49:1881–1892. doi: 10.1111/j.1528-1167.2008.01641.x. [DOI] [PubMed] [Google Scholar]
  • [36].Gean P.W., Huang C.C., Hung C.R., Tsai J.J. Valproic acid suppresses the synaptic response mediated by the NMDA receptors in rat amygdalar slices. Brain Res Bull. 1994;33:333–336. doi: 10.1016/0361-9230(94)90202-X. [DOI] [PubMed] [Google Scholar]

Articles from Neuroscience Bulletin are provided here courtesy of Springer

RESOURCES