Hippocampal CA3 pyramidal neurons receive synaptic inputs from commissural and associational fibers on both apical and basal dendrites. NMDA receptors at these synapses were examined in hippocampal slices of wild-type mice and GluR epsilon 1 (NR2A) subunit knockout mice. Electrical stimulations at the CA3 stratum radiatum or stratum oriens activate both commissural and associational (C/A).synapses, whereas stimulations at ventral fimbria mainly activate commissural synapses. Ro 25-6981 and ifenprodil, the GluR epsilon 2 (NR2B) subunit-selective NMDA receptor antagonists, suppressed NMDA receptor-mediated excitatory postsynaptic currents (NMDA EPSCs) at the commissural-CA3 synapses on basal dendrites more strongly than those at the C/A-CA3 synapses on apical or basal dendrites. However, glutamate-evoked NMDA receptor currents were reduced by the GluR epsilon 1 subunit knockout to a similar extent at both apical and basal dendrites. The GluR epsilon 1 subunit knockout also reduced NMDA EPSCs at the C/A-CA3 synapses on basal dendrites, but did not affect NMDA EPSCs at the commissural-CA3 synapses on basal dendrites. These results confirmed our previous findings that NMDA receptors operating at different synapses in CA3 pyramidal cells have different GluR epsilon subunit compositions, and further show that the GluR epsilon subunit composition may be regulated depending on the types of synaptic inputs, even within a single CA3 pyramidal neuron. (C) 2000 Elsevier Science Ltd. All rights reserved.