Adenosine A Receptors Shut Down Adenosine A Receptor-Mediated Presynaptic Inhibition to Promote Implementation of Hippocampal Long-Term Potentiation.

Adenosine operates a modulation system fine-tuning the efficiency of synaptic transmission and plasticity through A and A receptors (AR, AR), respectively. Supramaximal activation of AR can block hippocampal synaptic transmission, and the tonic engagement of AR-mediated inhibition is increased with increased frequency of nerve stimulation. This is compatible with an activity-dependent increase in extracellular adenosine in hippocampal excitatory synapses, which can reach levels sufficient to block synaptic transmission. We now report that AR activation decreases AR-medated inhibition of synaptic transmission, with particular relevance during high-frequency-induced long-term potentiation (LTP). Thus, whereas the AR antagonist DPCPX (50 nM) was devoid of effects on LTP magnitude, the addition of an AR antagonist SCH58261 (50 nM) allowed a facilitatory effect of DPCPX on LTP to be revealed. Additionally, the activation of AR with CGS21680 (30 nM) decreased the potency of the AR agonist CPA (6-60 nM) to inhibit hippocampal synaptic transmission in a manner prevented by SCH58261. These observations show that AR play a key role in dampening AR during high-frequency induction of hippocampal LTP. This provides a new framework for understanding how the powerful adenosine AR-mediated inhibition of excitatory transmission can be controlled to allow the implementation of hippocampal LTP.