ACTIVATION OF NMDA RECEPTORS IS NECESSARY FOR THE INDUCTION OF ASSOCIATIVE LONG-TERM POTENTIATION IN AREA CA1 OF THE RAT HIPPOCAMPAL SLICE

1. It is commonly assumed that the role of the strongly activated hete rosynaptic input during the induction of associative long-term potenti ation (LTP) is to relieve the magnesium blockade of NMDA receptors loc ated at the weakly stimulated synapses and thereby allow the weak inpu t to undergo potentiation. We tested this assumption by using a caged form of the NMDA receptor antagonist, D-(-)-2-amino-5-phosphonopentano ic acid (D-AP5) to block the activation of NMDA receptors at the weak input in a conditioning protocol for the induction of associative LTP in area CA1 of the rat hippocampal slice. 2. The effect of releasing D -AP5 by flash photolysis of 100 mu M caged D-AP5 (N-[1-(2-nitrophenyl) ethoxycarbonyl]-D-AP5) on pharmacologically isolated NMDA receptor-med iated field EPSPs was examined in area CA1. The slope of the EPSP was reduced by 71% within 50 ms of the initiation of the photolytic reacti on when the concentration of released D-AP5 had reached 2.0-2.5 mu M a nd was reduced by 95% within 1 min (10 mu m D-AP5 released). 3. Associ ative LTP was induced by pairing a strong tetanus to one input with a weak tetanus (subthreshold for homosynaptic LTP) to a second input. Th e strong tetanus preceded the weak by 50 ms. Rapid application of D-AP 5, by flash photolysis of caged D-AP5, coincident with the last shock of the strong tetanus, resulted in the blockade of NMDA receptor activ ation during the period of the weak tetanus. Associative LTP was block ed by photolysis of caged D-AP5 but was normally expressed in experime nts using caged L-AP5. 4. We conclude that activation of NMDA receptor s at the weakly activated input is an essential requirement for synapt ically induced associative LTP.