Adenosine A 2A Receptors Shut Down Adenosine A 1 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 1 and A 2A receptors (A 1 R, A 2A R), respectively. Supramaximal activation of A 1 R can block hippocampal synaptic transmission, and the tonic engagement of A 1 R-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 A 2A R activation decreases A 1 R-medated inhibition of synaptic transmission, with particular relevance during high-frequency-induced long-term potentiation (LTP). Thus, whereas the A 1 R antagonist DPCPX (50 nM) was devoid of effects on LTP magnitude, the addition of an A 2A R antagonist SCH58261 (50 nM) allowed a facilitatory effect of DPCPX on LTP to be revealed. Additionally, the activation of A 2A R with CGS21680 (30 nM) decreased the potency of the A 1 R agonist CPA (6-60 nM) to inhibit hippocampal synaptic transmission in a manner prevented by SCH58261. These observations show that A 2A R play a key role in dampening A 1 R during high-frequency induction of hippocampal LTP. This provides a new framework for understanding how the powerful adenosine A 1 R-mediated inhibition of excitatory transmission can be controlled to allow the implementation of hippocampal LTP.