NMDA‐dependent heterosynaptic long‐term depression in the dentate gyrus of anaesthetized rats

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Abstract
This report examines the inductive mechanism involved in long-term heterosynaptic depression (LTD) in the dentate gyrus of anaesthetized rats. Associative and non-associative stimulus protocols were implemented, using the ipsilateral medial and lateral perforant path inputs to the dentate gyrus as the test pathways. In all experiments, the medial perforant path (MPP) received the conditioning stimuli which consisted of eight stimulus trains of 2 s duration, spaced 1 minute apart. Within each train the stimuli occurred as a burst of 5 pulses at 100 Hz, repeated at 200 ms intervals. The lateral perforant path (LPP) served as the test pathway in all of the initial experiments. In the associative condition, it received single pulses equally spaced between the medial path bursts. In the non-associative condition, no lateral path stimuli were given during the medial path trains, In both condition, the application of the conditioning stimuli resulted in a long-term potentiation (LTP) of the medial path evoked responses (P < 0.001), while the lateral path responses showed LTD (P < 0.001). A two-way analyses of variance revealed there to be no difference between the two paradigms in the expression of LTP or LTD in naive pathways or in their ability to depress a potentiated pathway (P > 0.05) An occlusion test also showed there to be no further decreases in synaptic efficacy with the associative paradigm after the lateral path synapses were saturated with non-associative LTD. The N-methyl-D-aspartate (NMDA) receptor antagonist CPP (3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid; 10 mg/kg) blocked the appearance of LTP and LTD in both conditions, and in fact, the lateral path responses in the associative condition actually showed a significant degree of enhancement (P < 0.001). This enhancement was also evidenced when the lateral path stimuli were administered alone without prior CPP administration (P < 0.05). The results imply that one set of common mechanisms is utilized in the induction of LTD in the dentate gyrus, whether the medial and lateral paths are activated in an associative or a non-associative manner.