How does adenosine control neuronal dysfunction and neurodegeneration?

The adenosine modulation system mostly operates through inhibitory A1 (A1 R) and facilitatory A2A receptors (A2A R) in the brain. The activity-dependent release of adenosine acts as a brake of excitatory transmission through A1 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 A2A R; A2A R switch off A1 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. A1 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, A1 R trigger preconditioning, which may limit the spread of damage. Brain insults also up-regulate A2A R, probably to bolster adaptive changes, but this heightens brain damage since A2A R blockade affords neuroprotection in models of epilepsy, depression, Alzheimer's, or Parkinson's disease. This initially involves a control of synaptotoxicity by neuronal A2A R, whereas astrocytic and microglia A2A R might control the spread of damage. The A2A R signaling mechanisms are largely unknown since A2A 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 A1 R preconditioning and preventing excessive A2A 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 A2A receptors (A2A R) in the synapse undergoing an alteration of synaptic efficiency with an increased inhibitory action of A1 R in all surrounding synapses. Brain insults trigger an up-regulation of A2A R in an attempt to bolster adaptive plasticity together with adenosine release and A1 R desensitization; this favors synaptotocity (increased A2A R) and decreases the hurdle to undergo degeneration (decreased A1 R). Maximal neuroprotection is expected to result from a combined A2A R blockade and increased A1 R activation. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases".