Selective Abolition of the NMDA Component of Long-Term Potentiation in Mice Lacking mGluR5

  1. Zhengping Jia1,
  2. YouMing Lu1,
  3. Jeff Henderson1,
  4. Franco Taverna1,
  5. Carmelo Romano2,
  6. Wanda Abramow-Newerly1,
  7. J. Martin Wojtowicz3, and
  8. John Roder1,4
  1. 1Program in Development & Fetal Health, Samuel Lunenfeld Research Institute, Toronto, Ontario M5G 1X5, Canada, Department of Molecular and Medical Genetics, University of Toronto, Toronto M5S 1A8, Canada, 2Department of Anatomy and Neurobiology, Washington University, St. Louis, Missouri 63110 USA, 3Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Abstract

The mechanisms underlying the differential expression of long-term potentiation (LTP) by AMPA and NMDA receptors, are unknown, but could involve G-protein-linked metabotropic glutamate receptors. To investigate this hypothesis we created mutant mice that expressed no metabotropic glutamate receptor 5 (mGluR5), but showed normal development. In an earlier study of these mice we analyzed field-excitatory postsynaptic potential (fEPSPs) in CA1 region of the hippocampus and found a small decrease; possibly arising from changes in the NMDAR-mediated component of synaptic transmission. In the present study we used whole-cell patch clamp recordings of evoked excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons to identify the AMPAR- and NMDAR-mediated components of LTP. Recordings from control mice following tetanus, or agonist application (IS, 3R-1-amino-cyclopentane 1,3-dicarboxylic acid) (ACPD), revealed equal enhancement of the AMPA and NMDA receptor-mediated components. In contrast, CA1 neurons from mGluR5-deficient mice showed a complete loss of the NMDA-receptor-mediated component of LTP (LTPNMDA), but normal LTP of the AMPA-receptor-mediated component (LTPAMPA). This selective loss of LTPNMDA was seen in three different genotypic backgrounds and was apparent at all holding potentials (−70 mV to +20 mV). Furthermore, the LTPNMDA deficit in mGluR5 mutant mice could be rescued by stimulating protein kinase C (PKC) with 4β-phorbol-12,13-dibutyrate (PDBu). These results suggest that PKC may couple the postsynaptic mGluR5 to the NMDA-receptor potentiation during LTP, and that this signaling mechanism is distinct from LTPAMPA. Differential enhancement of AMPAR and NMDA receptors by mGluR5 also supports a postsynaptic locus for LTP.

Footnotes

  • 4 Corresponding author.

    • Received February 19, 1998.
    • Accepted July 17, 1998.
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