Skip to main content
SpringerLink
Log in

Impaired activation of CA3 pyramidal neurons in the epileptic hippocampus

  • Original Article
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

Abstract

We employed in vitro and ex vivo imaging tools to characterize the function of limbic neuron networks in pilocarpine-treated and age-matched, nonepileptic control (NEC) rats. Pilocarpinetreated animals represent an established model of mesial temporal lobe epilepsy. Intrinsic optical signal (IOS) analysis of hippocampal-entorhinal cortex (EC) slices obtained from epileptic rats 3 wk after pilocarpine-induced status epilepticus (SE) revealed hyperexcitability in many limbic areas, but not in CA3 and medial EC layer III. By visualizing immunopositivity for FosB/ΔFosBrelated proteins—which accumulate in the nuclei of neurons activated by seizures—we found that: (1) 24 h after SE, FosB/ΔFosB immunoreactivity was absent in medial EC layer III, but abundant in dentate gyrus, hippocampus proper (including CA3) and subiculum; (2) FosB/ΔFosB levels progressively diminished 3 and 7 d after SE, whereas remaining elevated (p<0.01) in subiculum; (3) FosB/ΔFosB levels sharply increased 2 wk after SE (and remained elevated up to 3 wk) in dentate gyrus and in most of the other areas but not in CA3. A conspicuous neuronal damage was noticed in medial EC layer III, whereas hippocampus was more preserved. IOS analysis of the stimulus-induced responses in slices 3 wk after SE demonstrated that IOSs in CA3 were lower (p<0.05) than in NEC slices following dentate gyrus stimulation, but not when stimuli were delivered in CA3. These findings indicate that CA3 networks are hypoactive in comparision with other epileptic limbic areas. We propose that this feature may affect the ability of hippocampal outputs to control epileptiform synchronization in EC.

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

Similar content being viewed by others

References

  • Andersson M., Hilbertson A., and Cenci M. A. (1999) Striatal fosB expression is causally linked with l-DOPA-induced abnormal involuntary movements and the associated upregulation of striatal prodynorphin mRNA in a rat model of Parkinson’s disease. Neurobiol. Dis. 6, 461–474.

    Article  PubMed  CAS  Google Scholar 

  • André V., Ferrandon A., Marescaux C., and Nehlig A. (2000) The lesional and epileptogenic consequences of lithium-pilocarpine-induced status epilepticus are affected by previous exposure to isolated seizures: effects of amygdala kindling and maximal electroshocks. Neuroscience 99, 469–481.

    Article  PubMed  Google Scholar 

  • Andrew R. D., Adams J. R., and Polischuk T. M. (1996) Imaging kainate and NMDA-induced intrinsic optical signals from the hippocampal slice. J. Neurophysiol. 76, 2707–2717.

    PubMed  CAS  Google Scholar 

  • Avoli M., D’Antuono M., Louvel J., et al. (2002) Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system. Prog. Neurobiol. 68, 167–207.

    Article  PubMed  CAS  Google Scholar 

  • Barbarosie M. and Avoli M. (1997) CA3-driven hippocampal-entorhinal loop controls rather than sustains in vitro limbic seizures. J. Neurosci. 17, 9308–9314.

    PubMed  CAS  Google Scholar 

  • Barbarosie M., Louvel J., Kurcewicz I., and Avoli M. (2000) CA3-released entorhinal seizures disclose dentate gyrus epileptogenicity and unmask a temporoammonic pathway. J. Neurophysiol. 83, 1115–1124.

    PubMed  CAS  Google Scholar 

  • Barbarosie M., Louvel J., D’Antuono M., Kurcewicz I., and Avoli M. (2002) Masking synchronous GABA-mediated potentials controls limbic seizures. Epilepsia 43, 1469–1479.

    Article  PubMed  Google Scholar 

  • Bartolomei F., Wendling F., Bellanger J. J., Regis J., and Chauvel P. (2001) Neural networks involving the medial temporal structures in temporal lobe epilepsy. Clin. Neurophysiol. 112, 1746–1760.

    Article  PubMed  CAS  Google Scholar 

  • Biagini G., Pich E. M., Carani C., et al. (1993) Indole-pyruvic acid, a tryptophan ketoanalogue, antagonizes the endocrine but not the behavioral effects of repeated stress in a model of depression. Biol. Psychiatry 33, 712–719.

    Article  PubMed  CAS  Google Scholar 

  • Biagini G., Babinski K., Avoli M., Marcinkiewicz M., and Sequela P. (2001) Regional and subunit-specific downregulation of acid-sensing ion channels in the pilocarpine model of epilepsy. Neurobiol. Dis. 8, 45–58.

    Article  PubMed  CAS  Google Scholar 

  • Bragdon A. C., Kojima H., and Wilson W. A. (1992) Suppression of interictal bursting in hippocampus unleashes seizures in entorhinal cortex: a proepileptic effect of lowering [K+]o and raising [Ca2+]o. Brain Res. 590, 128–135.

    Article  PubMed  CAS  Google Scholar 

  • Chase T. D., Carrey N., Brown R. E., and Wilkinson M. (2005) Methylphenidate differentially regulates c-fos and fosB expression in the developing rat striatum. Dev. Brain Res. 157, 181–191.

    Article  CAS  Google Scholar 

  • Chen J., Kelz M. B., Hope B. T., Nakabeppu Y., and Nestler E. J. (1997) Chronic Fos-related antigens: stable variants of ΔFosB induced in brain by chronic treatments. J. Neurosci. 17, 4933–4941.

    PubMed  CAS  Google Scholar 

  • D’Antuono M., Benini R., Biagini G., et al. (2002) Limbic network interactions leading to hyperexcitability in a model of temporal lobe epilepsy. J. Neurophysiol. 87, 634–639.

    PubMed  Google Scholar 

  • D’Arcangelo G., Tancredi V., and Avoli M. (2001) Intrinsic optical signals and electrographic seizures in the rat limbic system. Neurobiol. Dis. 8, 993–1005.

    Article  PubMed  CAS  Google Scholar 

  • D’Arcangelo G., Panuccio G., Tancredi V., and Avoli M. (2005) Repetitive low-frequency stimulation reduces epileptiform synchronization in limbic neuronal networks. Neurobiol. Dis. 19, 119–128.

    Article  PubMed  CAS  Google Scholar 

  • Dalby N. O. and Mody I. (2001) The process of epileptogenesis: a pathophysiological approach. Cur. Op. Neurol. 14, 187–192.

    Article  CAS  Google Scholar 

  • de Curtis M. and Avanzini G. (2001) Interictal spikes in focal epileptogenesis. Prog. Neurobiol. 63, 541–567.

    Article  PubMed  Google Scholar 

  • Du F., Eid T., Lothman E. W., Köhler C., and Schwarcz R. (1995) Preferential neuronal loss in layer III of the medial entorhinal cortex in rat models of temporal lobe epilepsy. J. Neurosci. 15, 6301–6313.

    PubMed  CAS  Google Scholar 

  • Esclapez M., Hirsch J. C., Ben-Ari Y., and Bernard C. (1999) Newly formed excitatory pathways provide a substrate for hyperexcitability in experimental temporallobe epilepsy. J. Comp. Neurol. 408, 449–460.

    Article  PubMed  CAS  Google Scholar 

  • Fabene P. F., Marzola P., Sbarbati A., and Bentivoglio M. (2003) Magnetic resonance imaging of changes elicited by status epilepticus in the rat brain: diffusion-weighted and T2-weighted images, regional blood volume maps, and direct correlation with tissue and cell damage. Neuroimage 18, 375–389.

    Article  PubMed  CAS  Google Scholar 

  • Gloor P. (1997) The Temporal Lobe and Limbic System. Oxford University Press, New York.

    Google Scholar 

  • Goussakov I. V., Fink K., Elger C. E., and Beck H. (2000) Metaplasticity of mossy fiber synaptic transmission involves altered release probability. J. Neurosci. 20, 3434–3441.

    PubMed  CAS  Google Scholar 

  • Gutierrez R. (2003) The GABAergic phenotype of the “glutamatergic” granule cells of the dentate gyrus. Prog. Neurobiol. 71, 337–358.

    Article  PubMed  CAS  Google Scholar 

  • Hauser W. A. and Kurland L. T. (1975) The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia 16, 1–66.

    PubMed  CAS  Google Scholar 

  • Jarvis C. R., Lilge L., Vipond G. J., and Andrew R. D. (1999) Interpretation of intrinsic optical signals and calcein fluorescence during acute excitotoxic insult in the hippocampal slice. Neuroimage 10, 357–372.

    Article  PubMed  CAS  Google Scholar 

  • Jefferys J. G. (1999) Hippocampal sclerosis and temporal lobe epilepsy: cause or consequence? [Editorial]. Brain 122, 1007–1008.

    Article  PubMed  Google Scholar 

  • Ji L. L., Fleming T., Penny M. L., Toney G. M., and Cunningham J. T. (2005) Effects of water deprivation and rehydration on c-Fos and FosB staining in the rat supraoptic nucleus and lamina terminalis region. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, R311-R321.

    PubMed  CAS  Google Scholar 

  • Kohler C. (1988) Intrinsic connections of the retrohippocampal region in the rat brain. III. The lateral entorhinal cortex. J. Comp. Neurol. 271, 208–228.

    Article  PubMed  CAS  Google Scholar 

  • Köhling R., Lucke A., Nagao T., Speckmann E. J., and Avoli M. (1995) Extracellular potassium elevations in the hippocampus of rats with long-term pilocarpine seizures. Neurosci. Lett. 201, 87–91.

    Article  PubMed  Google Scholar 

  • Liu Z., Nagao T., Desjardins G. C., Gloor P., and Avoli M. (1994) Quantitative evaluation of neuronal loss in the dorsal hippocampus in rats with long-term pilocarpine seizures. Epilepsy Res. 17, 237–247.

    Article  PubMed  CAS  Google Scholar 

  • MacVicar B. and Hochman D. (1991) Imaging of synaptically evoked intrinsic optical signals in hippocampal slices. J. Neurosci. 11, 1458–1469.

    PubMed  CAS  Google Scholar 

  • Mathern G. W., Babb T. L., and Armstrong D. L. (1997) Hippocampal sclerosis. In: Engel J, Pedley T. A., eds. Epilepsy: A Comprehensive Textbook. Philadelphia (PA): Lippincott-Raven; 1997, pp. 133–155.

    Google Scholar 

  • McClung C. A., Ulery P. G., Perrotti L. I., Zachariou V., Berton O., and Nestler E. J. (2004) DeltaFosB: a molecular switch for long-term adaptation in the brain. Mol. Brain Res. 132, 146–154.

    Article  PubMed  CAS  Google Scholar 

  • McCormick D. A. and Contreras D. (2001) On the cellular and network bases of epileptic seizures. Annu. Rev. Physiol. 63, 815–846.

    Article  PubMed  CAS  Google Scholar 

  • McNamara J. O. (1994) Cellular and molecular basis of epilepsy. J. Neurosci. 14, 3413–3425.

    PubMed  CAS  Google Scholar 

  • Mikkonen M., Soininen H., Kalvianen R., et al. (1998) Remodeling of neuronal circuitries in human temporal lobe epilepsy: increased expression of highly polysialylated neural cell adhesion molecule in the hippocampus and the entorhinal cortex. Ann. Neurol. 44, 923–934.

    Article  PubMed  CAS  Google Scholar 

  • Mohapel P., Zhang X., Gillespie G. W., et al. (2001) Kindling of claustrum and insular cortex: comparison to perirhinal cortex in the rat. Eur. J. Neurosci. 13, 1501–1519.

    Article  PubMed  CAS  Google Scholar 

  • Morris T. A., Jafari N., and DeLorenzo R. J. (2000) Chronic DeltaFosB expression and increased AP-1 transcription factor binding are associated with the long term plasticity changes in epilepsy. Mol. Brain. Res. 79, 138–149.

    Article  PubMed  CAS  Google Scholar 

  • Naber P. A., Lopes da Silva F. H., and Witter M. P. (2001) Reciprocal connections between the entorhinal cortex and hippocampal fields CA1 and the subiculum are in register with the projections from CA1 and the subiculum. Hippocampus 11, 99–104.

    Article  PubMed  CAS  Google Scholar 

  • Nagao T., Avoli M., and Gloor P. (1994) Interictal discharges in the hippocampus of rats with long-term pilocarpine seizures. Neurosci. Lett. 174, 160–164.

    Article  PubMed  CAS  Google Scholar 

  • Nagao T., Alonso A., and Avoli M. (1996) Epileptiform activity induced by pilocarpine in the rat hippocampal-entorhinal slice preparation. Neuroscience 72, 399–408.

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G. and Watson C. (1998) The Rat Brain in Stereotaxic Coordinates. Fourth ed. Academic, San Diego.

    Google Scholar 

  • Racine R. J. (1972) Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr. Clin. Neurophysiol. 32, 281–294.

    Article  PubMed  CAS  Google Scholar 

  • Rutecki P. A., Grossman R. G., Armstrong D., and Irish-Loewen S. (1989) Electrophysiological connections between the hippocampus and entorhinal cortex in patients with complex partial seizures. J. Neurosurg. 70, 667–675.

    Article  PubMed  CAS  Google Scholar 

  • Schmued L. C., Albertson C., and Slikker W. Jr. (1997) Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration. Brain Res. 751, 37–46.

    Article  PubMed  CAS  Google Scholar 

  • Spencer S. S. and Spencer D. D. (1994) Entorhinal-hippocampal interactions in medial temporal lobe epilepsy. Epilepsia 35, 721–727.

    Article  PubMed  CAS  Google Scholar 

  • Swartzwelder H. S., Lewis D. V., Anderson W. W., and Wilson W. A. (1987) Seizure-like events in brain slices: suppression by interictal activity. Brain Res. 410, 362–366.

    Article  PubMed  CAS  Google Scholar 

  • Traynelis S. F. and Dingledine R. (1988) Potassium-induced spontaneous electrographic seizures in the rat hippocampal slice. J. Neurophysiol. 59, 259–276.

    PubMed  CAS  Google Scholar 

  • Turski W. A., Cavalheiro E. A., Schwarz M., Czuczwar S. J., Kleinrok Z., and Turski L. (1983) Limbic seizures produced by pilocarpine in rats: behavioral, electroencephalographic and neuropathological study. Behav. Brain Res. 9, 315–335.

    Article  PubMed  CAS  Google Scholar 

  • Weissinger F., Buchheim K., Siegmund H., and Meierkord H. (2005) Seizure spread through the life cycle: optical imaging in combined brain slices from immature, adult, and senile rats in vitro. Neurobiol. Dis. 19, 84–95.

    Article  PubMed  Google Scholar 

  • Werme M., Messer C., Olson L., et al. (2002) ΔFosB regulates wheel running. J. Neurosci. 22, 8133–8138.

    PubMed  CAS  Google Scholar 

  • Wiebe S., Blume W. T., Girvin J. P., and Eliasziw M. (2001) A randomized, controlled trial of surgery for temporal lobe epilepsy. N. Engl. J. Med. 345, 311–318.

    Article  PubMed  CAS  Google Scholar 

  • Wilson W. A., Swartzwelder H. S., Anderson W. W., and Lewis D. V. (1988) Seizure activity in vitro: a dual focus model. Epilepsy Res. 2, 289–293.

    Article  PubMed  CAS  Google Scholar 

  • Witter M. P., Griffioen A. W., Jorritsma-Byham B., and Krijnen J. L. (1988) Entorhinal projections to the hippocampal CA1 region in the rat: an underestimated pathway. Neurosci. Lett. 85, 193–198.

    Article  PubMed  CAS  Google Scholar 

  • Witter M. P., Groenewegen H. J., Lopes da Silva F. H., and Lohman A. H. M. (1989) Functional organization of the extrinsic and intrinsic circuitry of the parahippocampal region. Prog. Neurobiol. 33, 161–253.

    Article  PubMed  CAS  Google Scholar 

  • Wozny C., Gabriel S., Jandova K., Schulze K., Heinemann U., and Behr J. (2005) Entorhinal cortex entrains epileptiform activity in CA1 in pilocarpine-treated rats. Neurobiol. Dis. 19, 451–460.

    Article  PubMed  CAS  Google Scholar 

  • Wu K. and Leung L. S. (2001) Enhanced but fragile inhibition in the dentate gyrus in vivo in the kainic acid model of temporal lobe epilepsy: a study using current source density analysis. Neuroscience 104, 379–396.

    Article  PubMed  CAS  Google Scholar 

  • Wu K. and Leung L. S. (2003) Increased dendritic excitability in hippocampal CA1 in vivo in the kainic acid model of temporal lobe epilepsy: a study using current source density analysis. Neuroscience 116, 599–616.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dipartimento di Scienze Biomediche, Università di Modena e Reggio Emilia, 41100, Modena, Italy

    Giuseppe Biagini & Enrica Baldelli

  2. Dipartimento di Neuroscienze, Università di Roma ‘Tor Vergata,’, 00173, Roma, Italy

    Giovanna D’Arcangelo & Virginia Tancredi

  3. Montreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University, H3A 2B4, Montreal, QC, Canada

    Margherita D’Antuono & Massimo Avoli

  4. Dipartimento di Fisiologia Umana e Farmacologia ‘V. Erspamer,’, Università di Roma ‘La Sapienza,’, 00185, Roma, Italy

    Massimo Avoli

Authors
  1. Giuseppe Biagini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giovanna D’Arcangelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Enrica Baldelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Margherita D’Antuono
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Virginia Tancredi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Massimo Avoli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Massimo Avoli.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Biagini, G., D’Arcangelo, G., Baldelli, E. et al. Impaired activation of CA3 pyramidal neurons in the epileptic hippocampus. Neuromol Med 7, 325–342 (2005). https://doi.org/10.1385/NMM:7:4:325

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/NMM:7:4:325

Index Entries

Search

Navigation