How does adenosine control neuronal dysfunction and neurodegeneration?

The adenosine modulation system mostly operates through inhibitory A 1 (A 1 R) and facilitatory A 2A receptors (A 2A R) in the brain. The activity‐dependent release of adenosine acts as a brake of excitatory transmission through A 1 R, 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 2A R; A 2A R switch off A 1 R 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. A 1 R are a hurdle for damage initiation, but they desensitize upon prolonged activation. However, if the insult is near‐threshold and/or of short‐duration, A 1 R trigger preconditioning, which may limit the spread of damage. Brain insults also up‐regulate A 2A R, probably to bolster adaptive changes, but this heightens brain damage since A 2A R blockade affords neuroprotection in models of epilepsy, depression, Alzheimer's, or Parkinson's disease. This initially involves a control of synaptotoxicity by neuronal A 2A R, whereas astrocytic and microglia A 2A R might control the spread of damage. The A 2A R signaling mechanisms are largely unknown since A 2A R 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 A 1 R preconditioning and preventing excessive A 2A R 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 2A R) in the synapse undergoing an alteration of synaptic efficiency with an increased inhibitory action of A 1 R in all surrounding synapses. Brain insults trigger an up‐regulation of A 2A R in an attempt to bolster adaptive plasticity together with adenosine release and A 1 R desensitization; this favors synaptotocity (increased A 2A R) and decreases the hurdle to undergo degeneration (decreased A 1 R). Maximal neuroprotection is expected to result from a combined A 2A R blockade and increased A 1 R activation. This article is part of a mini review series: “Synaptic Function and Dysfunction in Brain Diseases”.