Kainate-induced seizures alter protein composition and N-methyl-D-aspartate receptor function of rat forebrain postsynaptic densities

U. Wyneken, K. H. Smalla, J. J. Marengo, D. Soto, A. De la Cerda, W. Tischmeyer, R. Grimm, T. M. Boeckers, G. Wolf, F. Orrego, E. D. Gundelfinger

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74 Scopus citations

Abstract

The postsynaptic density is a highly dynamic structure, which is reorganized in an activity-dependent manner. An animal model for temporal lobe epilepsy, i.e. kainate-induced limbic seizures in rats, was used to study changes in postsynaptic density composition after extensive synaptic activity. Six hours after kainate injection, the protein content of the postsynaptic density fractions from rats that developed strong seizures was increased three-fold compared to saline-treated controls. Immunoblot analysis revealed that the relative amounts of metabotropic glutamate receptor 1α, N-ethylmaleimide-sensitive fusion protein, protein kinases C, Fyn and TrkB, as well as the neuronal nitric oxide synthase, were significantly higher in seizure-developing than in control rats. In contrast, the relative contents of the kainate receptor KA2 subunit, β-actin, α-adducin and the membrane-associated guanylate kinase homolog SAP90/PSD-95 were decreased. The relative amounts of additional postsynaptic density proteins, including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate and N-methyl-D-aspartate receptor subunits, calcium/calmodulin-dependent kinase type II, casein kinase 2, tubulin, microtubule-associated protein 2B, the membrane-associated guanylate kinase homolog SAP102, and proline-rich synapse-associated protein 1/cortactin binding protein 1/Shank2 remained essentially unchanged. To assess possible changes in postsynaptic performance, postsynaptic densities were isolated from control and epileptic rats, incorporated into giant liposomes and N-methyl-d-aspartate receptor currents were recorded. A significant reduction in the mean conductance was observed in patches containing postsynaptic densities from animals with high seizure activity. This was due to the presence of reduced conductance levels in each membrane patch compared to control postsynaptic density preparations. From these data, we suggest that intense synaptic activity associated with seizures modifies the composition of postsynaptic densities and has profound consequences on the function of the N-methyl-d-aspartate receptors present in them. This rearrangement may accompany impairment of synaptic plasticity.

Original languageEnglish
Pages (from-to)65-74
Number of pages10
JournalNeuroscience
Volume102
Issue number1
DOIs
StatePublished - 2 Jan 2001

Bibliographical note

Funding Information:
We are grateful to Kathrin Zobel, Anne Tiedge and Christa Otto for expert technical assistance, and to Dr Ricardo Bull for discussions on our electropysiological data. This work has been supported by the Volkswagen-Stiftung (U.W., F.O. and E.D.G.), Proyecto Fondecyt 1980063 (F.O. and U.W.), Proyecto MED 004 Universidad de los Andes (U.W.), Deutsche Forschungsgemeinschaft and Fonds der Chemischen Industrie (E.D.G.)

Keywords

  • Epilepsy
  • Glutamate receptor
  • Protein kinases
  • SAP90/PSD-95
  • Synapse
  • Synaptic plasticity

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