Elsevier

Neuroscience

Volume 113, Issue 3, 2 September 2002, Pages 617-628
Neuroscience

Cooperativity between extracellular adenosine 5′-triphosphate and activation of N-methyl-D-aspartate receptors in long-term potentiation induction in hippocampal CA1 neurons

https://doi.org/10.1016/S0306-4522(02)00190-2Get rights and content

Abstract

The mechanism of ATP-induced long-term potentiation (LTP) was studied pharmacologically using guinea-pig hippocampal slices. LTP, induced in CA1 neurons by 10 min application of 10 μM ATP, was blocked by co-application of the N-methyl-D-aspartate (NMDA) receptor antagonist, D,L-2-amino-5-phosphonovalerate (5 or 50 μM). In ATP-induced LTP, the delivery of test synaptic inputs (once every 20 s) to CA1 neurons could be replaced by co-application of NMDA (100 nM) during ATP perfusion. These results suggest that, in CA1 neurons, a co-operative effect between extracellular ATP and activation of NMDA receptors is required to trigger the process involved in ATP-induced LTP. In addition, ATP-induced LTP was blocked by co-application of an ecto-protein kinase inhibitor, K-252b (40 or 200 nM), whereas a P2X purinoceptor antagonist, pyridoxal phosphate 6-azophenyl-2′,4′-disulfonic acid 4-sodium (50 μM), or a P2Y purinoceptor antagonist, basilen blue (10 μM), had no effect.

The results of the present study, therefore, indicate that the mechanisms of ATP-induced LTP involve the modulation of NMDA receptors/Ca2+ channels and the phosphorylation of extracellular domains of synaptic membrane proteins, one of which could be the NMDA receptor/Ca2+ channel.

Section snippets

Slice preparation

The animals used were maintained and handled following the guidelines of the Animal Care and Use Committee of the Yamagata University School of Medicine. Adult male Hartley guinea-pigs (250–300 g, Funabashi Farm Co., Tokyo, Japan) were killed by decapitation, then the hippocampi were quickly removed and cut into 500-μm-thick transverse slices using a rotary slicer (Dosaka DK-7700, Kyoto, Japan). Slices were pre-incubated for a minimum of 1 h at 30–32°C in a 95% O2/5% CO2 atmosphere in standard

ATP-induced LTP in hippocampal CA1 neurons

Perfusion for 10 min with 1–10 μM ATP caused a transient reduction in the response, which, after removal of ATP, was followed by a gradual increase to a potentiated plateau, which was maintained for at least 30 min (ATP-induced LTP). Figure 1A, B, which, respectively, show sample wave forms (upper traces) and the summarized results (main figure) for the S-EPSP and A-PS, clearly show that a robust LTP was induced in slices perfused with 10 μM ATP, but not to any significant level in those

Discussion

The results of the present study indicate that ATP-induced LTP in CA1 neurons is not due to decreased activity of inhibitory inter-neurons or to increased excitatory transmitter release from pre-synaptic terminals (Fig. 2), but is due to the activation of NMDA receptors/channels (Fig. 3). Thus, the formation of ATP-induced LTP occurs at a post-synaptic site at hippocampal CA1 synapses and involves NMDA receptors/channels. Previous studies on the rat nucleus accumbens (Harvey and Lacey, 1997)

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