The effects of angiotensin IV analogs on long-term potentiation within the CA1 region of the hippocampus in vitro

Within the brain-renin angiotensin system, it is generally assumed that angiotensin peptide fragments shorter than angiotensins II and III, including angiotensin IV (AngIV), are inactive. This belief has been challenged by the recent discovery that AngIV, and AngIV-like analogs, bind with high affinity and specificity to a putative angiotensin binding site termed AT 4. In the brain these sites include the hippocampus, cerebellum, and cerebral cortex, and influence associative and spatial learning tasks. The present study investigated the effects of two AngIV analogs, Nle 1-AngIV (an AT 4 receptor agonist) and Nle 1-Leual 3-AngIV (an AT 4 receptor antagonist), on long-term potentiation (LTP). Field excitatory postsynaptic potentials (fEPSPs) were recorded from the CA1 stratum radiatum following stimulation of the Schaffer collateral pathway. Activation of AT 4 receptors by Nle 1-AngIV enhanced synaptic transmission during low-frequency test pulses (0.1 Hz), and increased the level of tetanus-induced LTP by 63% over that measured under control conditions. Paired stimulation before and during infusion of Nle 1-AngIV indicated no change in paired-pulse facilitation (PPF) as a result of AT 4 receptor activation suggesting that the underlying mechanism(s) responsible for Nle 1-AngIV-induced increase in synaptic transmission and LTP is likely a postsynaptic event. Further, applications of Nle 1-Leual 3-AngIV prior to, but not 15 or 30 min after, tetanization prevented stabilization of LTP. These results extend previous findings from behavioral data in that AT 4 receptor agonists and antagonists are capable of activating, and inhibiting, learning and memory pathways in the hippocampus, and suggest that the AT 4 receptor subtype is involved in synaptic plasticity.