SELECTIVE ABOLITION OF THE NMDA COMPONENT OF LONG-TERM POTENTIATION IN MICE LACKING MGLUR5

The mechanisms underlying the differential expression of long-term pot entiation (LTP) by AMPA and NMDA receptors, are unknown, but could inv olve 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 e arlier study of these mice we analyzed field-excitatory postsynaptic p otential (fEPSPs) in CA1 region of the hippocampus and found a small d ecrease; possibly arising from changes in the NMDAR-mediated component of synaptic transmission. In the present study we used whole-cell pat ch clamp recordings of evoked excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons to identify the AMPAR- and NMDAR-mediated co mponents of LTP. Recordings from control mice following tetanus, or ag onist application (IS, 3R-1-amino-cyclopentane 1,3-dicarboxylic acid) (ACPD), revealed equal enhancement of the AMPA and NMDA receptor-media ted components. In contrast, CA1 neurons from mGluR5-deficient mice sh owed a complete loss of the NMDA-receptor-mediated component of LTP (L TPNMDA), but normal LTP of the AMPA-receptor-mediated component (LTPAM PA). This selective loss of LTP 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 r escued by stimulating protein kinase C (PKC) with 4 beta-phorbol-12,13 -dibutyrate (PDBu). These results suggest that PKC may couple the post synaptic mGluR5 to the NMDA-receptor potentiation during LTP, and that this signaling mechanism is distinct from LTPAMPA. Differential enhan cement of AMPAR and NMDA receptors by mGluR5 also supports a postsynap tic locus for LTP.