Adenosine A2A Receptors Shut Down Adenosine A1 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.