The dorsal CA3 region of the hippocampus is unique in its connectivity, sensitivity to neurotoxic lesions, and its ability to encode and retrieve episodic memories. Computational models of the CA3 region predict that blocking mossy-fiber and/or perforant path activity to CA3 would cause impairments in learning and recall of spatial memory, respectively. Because the CA3 region contains -opioid receptors and receives inputs from the mossy-fiber and lateral perforant pathways, both of which contain and release opioid peptides, we tested the hypothesis that inactivating -opioid receptors in the CA3 region would cause spatial learning and memory impairments and retrieval deficits. In this study, male Sprague Dawley rats were trained in a Morris water maze after a single bilateral intrahippocampal injection of either saline or the selective and irreversible -opioid receptor antagonist ␤-funaltrexamine (␤-FNA) into area CA3. We found that -opioid receptor binding decreased 24 hr after ␤-FNA injection and returned to control levels 11 d after injection. Injections of ␤-FNA into the CA3 region, but not into the ventricles, caused a significant impairment in the acquisition of spatial learning without causing sensory or motor deficits. New learning was not affected once -opioid receptor levels replenished (Ͼ11 d after injection). In pretrained animals, ␤-FNA significantly impaired spatial memory retrieval and new (reversal) learning. These data are consistent with theoretical models of CA3 function and suggest that CA3 -opioid receptors play an important role in the acquisition and retrieval of spatial memory.

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The effects of aging on long-term potentiation (LTP) in the dentate gyrus (DG) and CA1 are well documented, but LTP at the medial perforant path (MPP)-CA3 synapse of aged animals has remained unexplored. Because the MPP-DG and Schaffer-collateral-CA1 synapses account for only about 20% of total hippocampal synapses, global understanding of how aging affects hippocampal plasticity has remained limited. Much is known about LTP induction in the hippocampal formation, whereas the mechanisms that regulate LTP maintenance are less understood, especially during aging. We investigated the effects of aging on MPP-CA3 LTP induction and maintenance in awake rats. As is the case in the DG and CA1, high-frequency stimulation-induced LTP at the MPP-CA3 synapse is normal in aged rats. These data indicate that N-methyl-D-aspartate (NMDA) receptor-mediated processes are intact at the MPP-CA3 synapse in aged rats. In contrast, aging impaired the magnitude and duration of MPP-CA3 LTP over a period of days. Also, these data are consistent with reports that area CA3 is especially susceptible to age-related changes. Our data suggest that aging impairs mechanisms that regulate the late phase of MPP-CA3 LTP and contribute to a more global understanding of how aging affects hippocampal plasticity.

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