title: Selective abolition of the NMDA component of long-term potentiation in mice lacking mGluR5.
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 (LTP(NMDA)), but normal LTP of the AMPA-receptor-mediated component (LTP(AMPA)). This selective loss of LTP(NMDA) was seen in three different genotypic backgrounds and was apparent at all holding potentials (-70 mV to +20 mV). Furthermore, the LTP(NMDA) deficit in mGluR5 mutant mice could be rescued by stimulating protein kinase C (PKC) with 4beta-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 LTP(AMPA). Differential enhancement of AMPAR and NMDA receptors by mGluR5 also supports a postsynaptic locus for LTP.
authors.affiliation: Program in Development & Fetal Health, Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada.
authors.forename: Z
authors.initials: Z
authors.lastname: Jia
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.forename: J
authors.initials: J
authors.lastname: Henderson
authors.forename: F
authors.initials: F
authors.lastname: Taverna
authors.forename: C
authors.initials: C
authors.lastname: Romano
authors.forename: W
authors.initials: W
authors.lastname: Abramow-Newerly
authors.forename: J M
authors.initials: JM
authors.lastname: Wojtowicz
authors.forename: J
authors.initials: J
authors.lastname: Roder
mesh_terms: D000818:Animals; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D005091:Exons; D006624:Hippocampus / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D017966:Pyramidal Cells / Q000502:physiology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D015183:Restriction Mapping; D013045:Species Specificity
chemical_list: C578936:Grm5 protein, mouse; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016202:N-Methylaspartate