Long-term potentiation in direct perforant path projections to the hippocampal CA3 region in vivo

The perforant path constitutes the primary projection system relaying information from the neocortex to the hippocampal formation. Long-term synaptic potentiation (LTP) in the perforant path projections to the dentate gyrus is well characterized. However, surprisingly few studies have addressed the mechanisms underlying LTP induction in the direct perforant path projections to the hippocampus. Here we investigate the role of N-methyl-D-aspartate (NMDA) and opioid receptors in the induction of LTP in monosynaptic medial and lateral perforant path projections to the CA3 region in adult pentobarbital sodium-anesthetized rats. Similar to LTP observed at the medial perforant path-dentate gyrus synapse, medial perforant path-CA3 synapses display LTP that is blocked by both local and systemic administration of the competitive NMDA receptor antagonist (+/-)-3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid [(+/-)-CPP]. By contrast, LTP induced at the lateral perforant path-CA3 synapses is not blocked by either local or systemic administration of this NMDA receptor antagonist. The induction of LTP at lateral perforant path-CA3 synapses, which is blocked by the opioid receptor antagonist naloxone, is also blocked by the selective mu opioid receptor antagonist Cys(2)-Tyr(3)-Orn(5)-Pen(7)-amide (CTOP), but not the selective delta opioid receptor antagonist naltrindole (NTI). CTOP was without effect on the induction of medial perforant path-CA3 LTP. The selective sensitivity of lateral perforant path-CA3 LTP to mu-opioid receptor antagonists corresponds with the distribution of mu-opioid receptors within the stratum lacunosum-moleculare of area CA3 where perforant path projections to CA3 terminate. These data indicate that both lateral and medial perforant path projections to the CA3 region display LTP, and that LTP induction in medial and lateral perforant path-CA3 synapses are differentially sensitive to NMDA receptor and mu-opioid receptor antagonists. This suggests a role for opioid, but not NMDA receptors in the induction of LTP at lateral perforant path projections to the hippocampal formation.