1. It is commonly assumed that the role of the strongly activated heterosynaptic input during the induction of associative long-term potentiation (LTP) is to relieve the
magnesium blockade of
NMDA receptors located at the weakly stimulated synapses and thereby allow the weak input to undergo potentiation. We tested this assumption by using a caged form of the
NMDA receptor antagonist, D-(-)-2-amino-5-phosphonopentanoic
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 microM
caged D-AP5 (N-[1-(2-nitrophenyl)ethoxycarbonyl]-D-AP5) on pharmacologically isolated
NMDA receptor-mediated 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 reaction when the concentration of released D-AP5 had reached 2.0-2.5 microM and was reduced by 95% within 1 min (10 microM D-AP5 released). 3. Associative LTP was induced by pairing a strong
tetanus to one input with a weak
tetanus (subthreshold for homosynaptic LTP) to a second input. The strong
tetanus preceded the weak by 50 ms. Rapid application of D-AP5, by flash photolysis of
caged D-AP5, coincident with the last
shock of the strong
tetanus, resulted in the blockade of
NMDA receptor activation during the period of the weak
tetanus. Associative LTP was blocked by photolysis of
caged D-AP5 but was normally expressed in experiments using caged L-AP5. 4. We conclude that activation of
NMDA receptors at the weakly activated input is an essential requirement for synaptically induced associative LTP.