The adenosine modulation system mostly operates through inhibitory A₁ (A₁R) and facilitatory A_2A receptors (A_2AR) in the brain. The activity‐dependent release of adenosine acts as a brake of excitatory transmission through A₁R, which are enriched in glutamatergic terminals. Adenosine sharpens salience of information encoding in neuronal circuits: high‐frequency stimulation triggers ATP release in the ‘activated’ synapse, which is locally converted by ecto‐nucleotidases into adenosine to selectively activate A_2AR; A_2AR switch off A₁R and CB1 receptors, bolster glutamate release and NMDA receptors to assist increasing synaptic plasticity in the ‘activated’ synapse; the parallel engagement of the astrocytic syncytium releases adenosine further inhibiting neighboring synapses, thus sharpening the encoded plastic change. Brain insults trigger a large outflow of adenosine and ATP, as a danger signal. A₁R are a hurdle for damage initiation, but they desensitize upon prolonged activation. However, if the insult is near‐threshold and/or of short‐duration, A₁R trigger preconditioning, which may limit the spread of damage. Brain insults also up‐regulate A_2AR, probably to bolster adaptive changes, but this heightens brain damage since A_2AR blockade affords neuroprotection in models of epilepsy, depression, Alzheimer's, or Parkinson's disease. This initially involves a control of synaptotoxicity by neuronal A_2AR, whereas astrocytic and microglia A_2AR might control the spread of damage. The A_2AR signaling mechanisms are largely unknown since A_2AR are pleiotropic, coupling to different G proteins and non‐canonical pathways to control the viability of glutamatergic synapses, neuroinflammation, mitochondria function, and cytoskeleton dynamics. Thus, simultaneously bolstering A₁R preconditioning and preventing excessive A_2AR function might afford maximal neuroprotection.

The main physiological role of the adenosine modulation system is to sharp the salience of information encoding through a combined action of adenosine A_2A receptors (A_2AR) in the synapse undergoing an alteration of synaptic efficiency with an increased inhibitory action of A₁R in all surrounding synapses. Brain insults trigger an up‐regulation of A_2AR in an attempt to bolster adaptive plasticity together with adenosine release and A₁R desensitization; this favors synaptotocity (increased A_2AR) and decreases the hurdle to undergo degeneration (decreased A₁R). Maximal neuroprotection is expected to result from a combined A_2AR blockade and increased A₁R activation.

This article is part of a mini review series: “Synaptic Function and Dysfunction in Brain Diseases”.