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Published in: NeuroMolecular Medicine 1/2018

01-03-2018 | Original Paper

NMDA Receptor GluN2 Subtypes Control Epileptiform Events in the Hippocampus

Authors: Pradeep Punnakkal, Deity Dominic

Published in: NeuroMolecular Medicine | Issue 1/2018

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Abstract

NMDA receptors (NMDARs) play a key role in synaptic plasticity and excitotoxicity. Subtype-specific role of NMDAR in neural disorders is an emerging area. Recent studies have revealed that mutations in NMDARs are a cause for epilepsy. Hippocampus is a known focal point for epilepsy. In hippocampus, expression of the NMDAR subtypes GluN1/GluN2A and GluN1/GluN2B is temporally regulated. However, the pharmacological significance of these subtypes is not well understood in epileptic context/models. To investigate this, epilepsy was induced in hippocampal slices by the application of artificial cerebrospinal fluid that contained high potassium but no magnesium. Epileptiform events (EFEs) were recorded from the CA1 and DG areas of hippocampus with or without subtype-specific antagonists. Irrespective of the age group, CA1 and DG showed epileptiform activity. The NMDAR antagonist AP5 was found to reduce the number of EFEs significantly. However, the application of subtype-specific antagonists (TCN 201 for GluN1/GluN2A and Ro 25-69811 for GluN1/GluN2B) revealed that EFEs had area-specific and temporal components. In slices from neonates, EFEs in CA1 were effectively reduced by Ro 25-69811, but were largely insensitive to TCN 201. In contrast, EFEs in DG were equally sensitive to both of the subtype-specific antagonists. However, the differential sensitivity for the antagonists observed in neonates was absent in later developmental stages. The study provides a functional insight into the NMDAR subtype-dependent contribution of EFEs in hippocampus of young rats, which may have implications in treating childhood epilepsy and avoiding unnecessary side effects of broad spectrum antagonists.
Literature
go back to reference Anderson, W. W., Lewis, D. V., Swartzwelder, H. S., & Wilson, W. A. (1986). Magnesium-free medium activates seizure-like events in the rat hippocampal slice. Brain Research, 398(1), 215–219.CrossRefPubMed Anderson, W. W., Lewis, D. V., Swartzwelder, H. S., & Wilson, W. A. (1986). Magnesium-free medium activates seizure-like events in the rat hippocampal slice. Brain Research, 398(1), 215–219.CrossRefPubMed
go back to reference Ashwood, T. J., & Wheal, H. V. (1987). The expression of N-methyl-D-aspartate-receptor-mediated component during epileptiform synaptic activity in hippocampus. British Journal of Pharmacology, 91(4), 815–822.CrossRefPubMedPubMedCentral Ashwood, T. J., & Wheal, H. V. (1987). The expression of N-methyl-D-aspartate-receptor-mediated component during epileptiform synaptic activity in hippocampus. British Journal of Pharmacology, 91(4), 815–822.CrossRefPubMedPubMedCentral
go back to reference Brady, R. J., Gorter, J. A., Monroe, M. T., & Swann, J. W. (1994). Developmental alterations in the sensitivity of hippocampal NMDA receptors to AP5. Brain Research. Developmental Brain Research, 83(2), 190–196.CrossRefPubMed Brady, R. J., Gorter, J. A., Monroe, M. T., & Swann, J. W. (1994). Developmental alterations in the sensitivity of hippocampal NMDA receptors to AP5. Brain Research. Developmental Brain Research, 83(2), 190–196.CrossRefPubMed
go back to reference Croucher, M. J., Collins, J. F., & Meldrum, B. S. (1982). Anticonvulsant action of excitatory amino acid antagonists. Science (New York, N.Y.), 216(4548), 899–901.CrossRef Croucher, M. J., Collins, J. F., & Meldrum, B. S. (1982). Anticonvulsant action of excitatory amino acid antagonists. Science (New York, N.Y.), 216(4548), 899–901.CrossRef
go back to reference Dzhala, V. I., & Staley, K. J. (2003). Transition from interictal to ictal activity in limbic networks in vitro. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 23(21), 7873–7880. Dzhala, V. I., & Staley, K. J. (2003). Transition from interictal to ictal activity in limbic networks in vitro. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 23(21), 7873–7880.
go back to reference Endele, S., Rosenberger, G., Geider, K., Popp, B., Tamer, C., Stefanova, I., et al. (2010). Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nature Genetics, 42(11), 1021–1026. https://doi.org/10.1038/ng.677.CrossRefPubMed Endele, S., Rosenberger, G., Geider, K., Popp, B., Tamer, C., Stefanova, I., et al. (2010). Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nature Genetics, 42(11), 1021–1026. https://​doi.​org/​10.​1038/​ng.​677.CrossRefPubMed
go back to reference Franck, J. E., Pokorny, J., Kunkel, D. D., & Schwartzkroin, P. A. (1995). Physiologic and morphologic characteristics of granule cell circuitry in human epileptic hippocampus. Epilepsia, 36(6), 543–558.CrossRefPubMed Franck, J. E., Pokorny, J., Kunkel, D. D., & Schwartzkroin, P. A. (1995). Physiologic and morphologic characteristics of granule cell circuitry in human epileptic hippocampus. Epilepsia, 36(6), 543–558.CrossRefPubMed
go back to reference Kumar, S. S., & Huguenard, J. R. (2003). Pathway-specific differences in subunit composition of synaptic NMDA receptors on pyramidal neurons in neocortex. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 23(31), 10074–10083. Kumar, S. S., & Huguenard, J. R. (2003). Pathway-specific differences in subunit composition of synaptic NMDA receptors on pyramidal neurons in neocortex. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 23(31), 10074–10083.
go back to reference Le Bail, M., Martineau, M., Sacchi, S., Yatsenko, N., Radzishevsky, I., Conrod, S., et al. (2015). Identity of the NMDA receptor coagonist is synapse specific and developmentally regulated in the hippocampus. Proceedings of the National Academy of Sciences of the United States of America, 112(2), E204–E213. https://doi.org/10.1073/pnas.1416668112.CrossRefPubMed Le Bail, M., Martineau, M., Sacchi, S., Yatsenko, N., Radzishevsky, I., Conrod, S., et al. (2015). Identity of the NMDA receptor coagonist is synapse specific and developmentally regulated in the hippocampus. Proceedings of the National Academy of Sciences of the United States of America, 112(2), E204–E213. https://​doi.​org/​10.​1073/​pnas.​1416668112.CrossRefPubMed
go back to reference Meldrum, B. (1984). Amino acid neurotransmitters and new approaches to anticonvulsant drug action. Epilepsia, 25(Suppl 2), S140–S149.CrossRefPubMed Meldrum, B. (1984). Amino acid neurotransmitters and new approaches to anticonvulsant drug action. Epilepsia, 25(Suppl 2), S140–S149.CrossRefPubMed
go back to reference Monyer, H., Burnashev, N., Laurie, D. J., Sakmann, B., & Seeburg, P. H. (1994). Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron, 12(3), 529–540.CrossRefPubMed Monyer, H., Burnashev, N., Laurie, D. J., Sakmann, B., & Seeburg, P. H. (1994). Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron, 12(3), 529–540.CrossRefPubMed
go back to reference Rutecki, P. A., Sayin, U., Yang, Y., & Hadar, E. (2002). Determinants of ictal epileptiform patterns in the hippocampal slice. Epilepsia, 43(Suppl 5), 179–183.CrossRefPubMed Rutecki, P. A., Sayin, U., Yang, Y., & Hadar, E. (2002). Determinants of ictal epileptiform patterns in the hippocampal slice. Epilepsia, 43(Suppl 5), 179–183.CrossRefPubMed
go back to reference Tsuda, M., Suzuki, T., & Misawa, M. (1997). Age-related decrease in the antiseizure effect of ifenprodil against pentylenetetrazole in mice. Brain Research. Developmental Brain Research, 104(1–2), 201–204.CrossRefPubMed Tsuda, M., Suzuki, T., & Misawa, M. (1997). Age-related decrease in the antiseizure effect of ifenprodil against pentylenetetrazole in mice. Brain Research. Developmental Brain Research, 104(1–2), 201–204.CrossRefPubMed
go back to reference Valenzuela, V., & Benardo, L. S. (1995). An in vitro model of persistent epileptiform activity in neocortex. Epilepsy Research, 21(3), 195–204.CrossRefPubMed Valenzuela, V., & Benardo, L. S. (1995). An in vitro model of persistent epileptiform activity in neocortex. Epilepsy Research, 21(3), 195–204.CrossRefPubMed
Metadata
Title
NMDA Receptor GluN2 Subtypes Control Epileptiform Events in the Hippocampus
Authors
Pradeep Punnakkal
Deity Dominic
Publication date
01-03-2018
Publisher
Springer US
Published in
NeuroMolecular Medicine / Issue 1/2018
Print ISSN: 1535-1084
Electronic ISSN: 1559-1174
DOI
https://doi.org/10.1007/s12017-018-8477-y

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