Adenosine A 2 receptors modulate hippocampal synaptic transmission via a cyclic-AMP-dependent pathway

Abstract

Blockade of adenosine A 2 receptors has been shown to significantly reduce the level of tetanus-induced long-term potentiation in area CA1 of rat hippocampus [Kessey K. et al. (1997) Brain Res. 756, 184–190; Sekino Y. et al. (1991) Biochem. biophys. Res. Commun. 181, 1010–1014]. In the present study, the effects of A 2 receptor activation and blockade on the modulation of normal synaptic transmission and tetanus-induced long-term potentiation were examined at the Schaffer–CA1 synapse in rat hippocampal slices. A 2 receptor activation reversibly enhanced synaptic transmission evoked by low-frequency test pulses as measured by the dendritic field excitatory postsynaptic potential. In the presence of A 1 receptor blockade, A 2 activation further enhanced the excitatory postsynaptic potential, while A 2 receptor blockade resulted in a reversible decrease of the excitatory postsynaptic potential. The A 2a receptor agonist, CGS21680, had no effect on the excitatory postsynaptic potential, suggesting that tonic activation of A 2b receptors contributes to synaptic transmission under normal physiological conditions. Furthermore, we investigated the contribution of A 2 receptors to the level of tetanus-induced long-term potentiation. Under control conditions, a single tetanus potentiated the excitatory postsynaptic potential by 63.5% relative to baseline 30 min post-tetanus. In contrast, tetanus-induced long-term potentiation during A 2 blockade was 21.3%. A 2 receptor activation increased the level of tetanus-induced long-term potentiation to 90.2%. Because A 2 receptors are known to stimulate cyclic-AMP accumulation, the possible involvement of cyclic-AMP was examined. Forskolin, a direct adenylate cyclase activator, and 8-bromo-cyclic-AMP, a membrane-permeable analog of cyclic-AMP, were able to reconstitute tetanus-induced long-term potentiation during A 2 receptor blockade; however, the inactive analog 1,9-dideoxy-forskolin had no effect, indicating that the effects of A 2 activation on synaptic transmission were mediated largely through the regulation of intracellular cyclic-AMP. Because A 1 receptors exert an opposing effect on synaptic transmission relative to A 2 receptors, these results suggest that the stoichiometry of A 1 versus A 2 receptor activation appears to play an important role in the modulation of normal synaptic transmission and long-term potentiation in the CA1 region of the hippocampus.