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