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 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(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.