Long-lasting enhancement of NMDA receptor-mediated synaptic transmission by metabotropic glutamate receptor activation

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Abstract
Synaptic transmission mediated by the N-methyl-D-aspartate (NMDA) glutamate receptor plays a key role in a range of plastic processes in the nervous system. These include long-term potentiation of synaptic transmission mediated by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor, neuronal development, excitotoxicity and certain learning tasks. Recently, long-term potentiation of NMDA receptor-mediated synaptic transmission was found to occur following high-frequency (tetanic) stimulation via an unknown mechanism. We show here that activation of metabotropic glutamate (mGlu) receptors by neurally released transmitter underlies this type of long-term potentiation. The whole-cell patch-clamp technique in the 'thick' slice of the rat dentate gyrus was used to measure NMDA receptor-mediated excitatory postsynaptic currents. We have found that mGlu receptor activation by a selective agonist produced a long-lasting enhancement which was mutually exclusive with long-term potentiation of these NMDA currents. Moreover, both forms of potentiation were greatly reduced by the mGlu receptor antagonists L-2-amino-3-phosphonopropionate and (R,S)-alpha-methyl-4-carboxyphenylglycine.