How does adenosine control neuronal dysfunction and neurodegeneration?

Abstract

The adenosine modulation system mostly operates through inhibitory A₁ (A₁ 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 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 A_2A R; A_2A 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 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 A₁ 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 A₁ 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 A₁ R desensitization; this favors synaptotocity (increased A_2A R) and decreases the hurdle to undergo degeneration (decreased A₁ R). Maximal neuroprotection is expected to result from a combined A_2A R blockade and increased A₁ R activation. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases".

Keywords: A1 receptor; A2A receptor; astrocyte; microglia; synaptic plasticity; synaptotoxicity.