title: How does adenosine control neuronal dysfunction and neurodegeneration?
abstract: The adenosine modulation system mostly operates through inhibitory A1(A1R) and facilitatory A2Areceptors (A2AR) 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 A2AR; A2AR 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 A2AR, probably to bolster adaptive changes, but this heightens brain damage since A2AR blockade affords neuroprotection in models of epilepsy, depression, Alzheimer's, or Parkinson's disease. This initially involves a control of synaptotoxicity by neuronal A2AR, whereas astrocytic and microglia A2AR might control the spread of damage. The A2AR signaling mechanisms are largely unknown since A2AR 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 A2AR 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 A2Areceptors (A2AR) 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 A2AR in an attempt to bolster adaptive plasticity together with adenosine release and A1R desensitization; this favors synaptotocity (increased A2AR) and decreases the hurdle to undergo degeneration (decreased A1R). Maximal neuroprotection is expected to result from a combined A2AR blockade and increased A1R activation. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases".
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|FMUC-Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Rodrigo A
authors.identifier: 0000-0003-2550-6422
authors.initials: RA
authors.lastname: Cunha
mesh_terms: D000241:Adenosine / Q000008:administration & dosage* / Q000378:metabolism*; D000818:Animals; D006801:Humans; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D058906:Purinergic P1 Receptor Agonists / Q000008:administration & dosage / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism
chemical_list: D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; D000241:Adenosine
keywords: A1 receptor; A2A receptor; astrocyte; microglia; synaptic plasticity; synaptotoxicity