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Neurological dysfunctions in mice expressing different levels of the Q/R site–unedited AMPAR subunit GluR–B

Nature Neuroscience volume 2, pages 57–64 (1999)Cite this article

Abstract

We generated mouse mutants with targeted AMPA receptor (AMPAR) GluR–B subunit alleles, functionally expressed at different levels and deficient in Q/R–site editing. All mutant lines had increased AMPAR calcium permeabilities in pyramidal neurons, and one showed elevated macroscopic conductances of these channels. The AMPAR–mediated calcium influx induced NMDA–receptor–independent long–term potentiation (LTP) in hippocampal pyramidal cell connections. Calcium–triggered neuronal death was not observed, but mutants had mild to severe neurological dysfunctions, including epilepsy and deficits in dendritic architecture. The seizure–prone phenotype correlated with an increase in the macroscopic conductance, as independently revealed by the effect of a transgene for a Q/R–site–altered GluR–B subunit. Thus, changes in GluR–B gene expression and Q/R site editing can affect critical architectural and functional aspects of excitatory principal neurons.

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Figure 1: Generation of GluR–B(Q)–expressing mice.
Figure 2: Calcium permeability and macroscopic conductance of AMPARs in pyramidal neurons.
Figure 3: NMDAR–independent LTP (a) Electrode arrangement.
Figure 4: Phenotypes and structural deficits in neuronal architecture.
Figure 5: Expression and effect of a GluR–B(N) transgene.

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Acknowledgements

We thank B. Sakmann and P. Andersen for discussions, R.J. Wenthold for antibodies, F. Schwenk for the deleter mouse, R. Pfeffer, A. Herold, M. Lang for technical assistance and M. Belovska, M. Kosma, S. Kranz for dendritic tree analysis. K.K. was recipient of an EMBO long–term fellowship. H.–C.K. was supported by Boehringer Ingelheim. This work was funded, in part, by grants from HFSP, the Volkswagenstiftung, the German Chemical Society and an unrestricted grant from Bristol–Meyers Squibb.

Author information

Author notes

  1. Kalev Kask

    Present address: AGY Therapeutics, Inc., c/o Tularik, Inc., Two Corporate Drive, South San Francisco, California, 94080, USA

  2. Rossella Brusa

    Present address: Schering Plough Research Institute, Via Olgettina 58, 20132, Milan, Italy

  3. Hans–Christian Kornau & Rohini Kolhekar

    Present address: BASF–LYNX Bioscience AG, Im Neuenheimer Feld 515, 69120, Heidelberg, Germany

Authors and Affiliations

  1. Department of Molecular Neurobiology, Max–Planck–Institute for Medical Research, Jahnstr. 29, Heidelberg, 69120, Germany

    Kalev Kask, Rossella Brusa, Hans–Christian Kornau, Rohini Kolhekar, Rolf Sprengel & Peter H. Seeburg

  2. Department of Molecular Cell Physiology, Max–Planck–Institute for Medical Research, Jahnstr. 29, Heidelberg, 69120, Germany

    Dirk Feldmeyer, Andrei Rozov & Nail Burnashev

  3. Institute of Neurophysiology, University of OsloL, P.O. Box 1104 Blindern, Oslo, N–0317, Norway

    Vidar Jensen & Øivind Hvalby

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Correspondence to Rolf Sprengel.

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Feldmeyer, D., Kask, K., Brusa, R. et al. Neurological dysfunctions in mice expressing different levels of the Q/R site–unedited AMPAR subunit GluR–B. Nat Neurosci 2, 57–64 (1999). https://doi.org/10.1038/4561

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