How does adenosine control neuronal dysfunction and neurodegeneration?

Abstract

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: highfrequency 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. Keywords: A 1 receptor, A 2A receptor, astrocyte, microglia, synaptic plasticity, synaptotoxicity. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases". Relevance of modulation systems to tune information flow in brain circuitsThe goal of understanding the flow of information in neuronal circuits has traditionally been centered in studying the key processes sustaining synaptic transmission and plasticity -i.e. the role of glutamate and glutamate receptors, as well as to a lesser extent the role of GABA and its receptors. If one considers an analogy to the experience of watching TV, this corresponds to studying how the ON/OFF button impacts all Received April 4, 2016; revised manuscript received May 23, 2016; accepted June 23, 2016. Address correspondence and reprint requests to R. A. Cunha, Center for Neurosciences and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal. E-mail: cunharod@gmail.com Abbreviations used: A 1 R, adenosine A 1 receptor; A 2A R, adenosine A 2A receptor; ADHD, attention deficit and hyperactivity disorder; BDNF, brain-derived neurotrophi...

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“…The adenosine modulation system mostly operates through inhibitory A1 receptors and facilitatory A2 receptors, and the adenosine receptors are mutually switching synaptic activities in the brain [34]. Brain insults up-regulate the adenosine A2a receptor through adaptive change of the brain, and adenosine A2a receptor bolsters neuronal plasticity.…”

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“…123 Under normal conditions, ATP released by astrocytic vesicles is rapidly converted to adenosine by ectonucleotidases and this occurs within the striatal spine module. 127,128 The effects of extracellular adenosine are primarily mediated by adenosine A 1 receptors (A 1 R) and A 2A R that are localized in the different locations of the striatal spine module. Both are G proteincoupled receptors (GPCRs), with A 1 R coupling to the inhibitory Gi/o protein and A 2A R coupling to the excitatory Gs/olf protein.…”

“…Both are G proteincoupled receptors (GPCRs), with A 1 R coupling to the inhibitory Gi/o protein and A 2A R coupling to the excitatory Gs/olf protein. 128 Both are co-localized in the glutamatergic terminals and astrocytes, where they form A 1 R-A 2A R heteromers. 129 These heteromers act as a concentrationdependent switch in the glutamatergic terminals, with activation of A 1 R inhibiting glutamate release, while activation of A 2A R shuts down A 1 R signaling and stimulates glutamate release.…”

“…This normally occurs when glutamatergic inputs are activated, leading to a release of ATP by neurons and glial cells that is later converted to adenosine by 5-nucleotidases. 128 When there is a phasic increase of adenosine, activation of A 2A R negatively modulates A 1 R signaling in the heteromer resulting in an increase in glutamate release. [130][131][132][133][134] This same interaction is also seen in cultured cortical astrocytes, where activation of the A 1 R-A 2A R heteromer has a modulatory effect on GABA uptake.…”

“…127 Extracellular ATP is rapidly converted to adenosine by a series of ectonucleotidases and extracellular levels of adenosine (adenosinergic tone) is maintained by the equilibrative transporter's and the astrocytic adenosine kinase's (ADK) ability to uptake and metabolize adenosine, respectively. 128,196 In mammals, there are two types of nucleoside transporters: bidirectional, equilibrative transporters that are driven by chemical gradients, and unidirectional, concentration transporters that are driven by sodium electrochemical gradients. 197 Adenosine uptake in the brain is mostly facilitated by the equilibrative nucleoside transporters, and when these transporters are blocked pharmacologically, adenosine accumulates in the extracellular space 128,197,198 Of the four equilibrative transporters identified (ENT1, ENT2, ENT3, and ENT4), ENT1 and ENT2 are the ones mostly present in the brain, expressed by both neurons and astrocytes.…”