Different cellular sources and different roles of adenosine: A1 receptor-mediated inhibition through astrocytic-driven volume transmission and synapse-restricted A2A receptor-mediated facilitation of plasticity.

Adenosine is a prototypical neuromodulator, which mainly controls excitatory transmission through the activation of widespread inhibitory A1 receptors and synaptically located A2A receptors. It was long thought that the predominant A1 receptor-meditated modulation by endogenous adenosine was a homeostatic process intrinsic to the synapse. New studies indicate that endogenous extracellular adenosine is originated as a consequence of the release of gliotransmitters, namely ATP, which sets a global inhibitory tonus in brain circuits rather than in a single synapse. Thus, this neuron-glia long-range communication can be viewed as a form of non-synaptic transmission (a concept introduced by Professor Sylvester Vizi), designed to reduce noise in a circuit. This neuron-glia-induced adenosine release is also responsible for exacerbating salient information through A1 receptor-mediated heterosynaptic depression, whereby the activation of a particular synapse recruits a neuron-glia network to generate extracellular adenosine that inhibits neighbouring non-tetanised synapses. In parallel, the local activation of facilitatory A2A receptors by adenosine, formed from ATP released only at high frequencies from neuronal vesicles, down-regulates A1 receptors and facilitates plasticity selectively in the tetanised synapse. Thus, upon high-frequency firing of a given pathway, the combined exacerbation of global A1 receptor-mediated inhibition in the circuit (heterosynaptic depression) with the local synaptic activation of A2A receptors in the activated synapse, cooperate to maximise salience between the activated and non-tetanised synapses.