Ireland DR, Abraham WC. Mechanisms of group I mGluR-dependent long-term depression of NMDA receptor-mediated transmission at Schaffer collateral-CA1 synapses. The mechanisms underlying group I metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) of N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic currents (EPSCs NMDAR ) are poorly understood. Here we investigated the effects of (R,S)-3,5-dihydroxyphenylglycine (DHPG), a selective agonist of group I mGluRs, on the

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... PSCs NMDAR in area CA1 of acute hippocampal slices from 6-to 8-wk Sprague-Dawley rats. DHPG acutely and persistently depressed the isolated EPSC NMDAR and transiently slowed its decay rate. Combined antagonism of mGluR1 and mGluR5 blocked the effects of DHPG. Strong calcium buffering with intracellular BAPTA did not reduce the acute depression or LTD, making the involvement of elevated postsynaptic calcium unlikely. The acute depression and LTD were not mediated by activation of tyrosine kinases or phosphatases, nor were they dependent on protein synthesis. However, the LTD was prevented by the intracellular actin-stabilizer jasplakinolide, raising the possibility that it was associated with a lateral movement of NMDARs. Supporting this hypothesis, when the effective spatial spread of synaptically released glutamate was increased using the glutamate transporter inhibitor TBOA, the resultant EPSC NMDAR did not undergo LTD in response to DHPG. Importantly, isolation of the extrasynaptic EPSC NMDAR by blockade of synaptic NMDARs with MK-801 showed that this was not due to a potentiation of the preexisting extrasynaptic component. These findings indicate that LTD of NMDAR-mediated synaptic transmission occurs via lateral movement of receptors away from the synapse.