The overall goal of this project is to evaluate the contribution of opioid and NMDA receptors in the induction of associative long term potentiation (LTP) in the major afferent systems of the CA3 region of the hippocampus. The CA3 region receives afferents displaying two forms of LTP induction: NMDA receptor and opioid receptor- dependent. Opioid receptor-dependent LTP is observed in medial perforant path and commissural projections to area CA3. Out initial studies show that mossy fiber projections to area CA3 display associative LTP, but associative mossy fiber LTP induction requires repetitive synaptic activity, which is necessary for the activation of opioid receptors. However, associative mossy fiber LTP also is blocked by NMDA receptor antagonists. Likewise, the induction of NMDA receptor-dependent LTP at medial perforant path-CA3 synapses is blocked by opioid receptor antagonists when it is induced by coactivation of opioidergic afferents. Our primary hypothesis is that both opioid and NMDA receptors contribute to associative LTP induction between synapses utilizing these different induction processes. The studies in specific aim 1 will determine if opioid and/or NMDA receptor antagonists alter associative LTP induction between the opioid receptor-dependent LTP at lateral perforant path-CA3 synapses and NMDA receptor-dependent medial perforant path-CA3 synapses using each projection as either the weakly stimulated (associated) or the strongly stimulated (conditioning) pathway. The studies in specific aim 2 will determine if associative LTP in opioidergic afferents is frequency-dependent by virtue of frequency-dependent opioid peptide release, and if associative LTP in afferents displaying opioid receptor-dependent LTP confer frequency-dependent constraints on LTP induction at non- opioidergic synapses. This will be determined by using a single- pulse associative paradigm, in which low frequency stimulation of one pathway is paired with high-frequency stimulation of another pathway in the presence of oioid receptor selective antagonists. The studies in specific aim 3 will determine if the optimal temporal parameters of associative interaction among CA3 afferents corresponds to the normal sequence of activation by CA3 afferents, and if opioid peptides contribute to this effect. These data will have implication regarding conditions in which associative information storage may normally occur among the afferent systems of the CA3 region. Because each pathway displays distinct requirements for associative LTP inductions, endogenous opioid peptides may confer both temporal and frequency-dependent constraints on the associative induction of LTP. This would suggest that the order of afferent activity and opioid peptide release may regulate virtually all associative information storage occurring among projections to the CA3 region of the hippocampus.
