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Adenosine receptors mainly control synaptic function, and excessive activation of adenosine receptors may worsen the onset of many neurological disorders. Accordingly, the regular intake of moderate doses of caffeine antagonizes adenosine receptors and affords robust neuroprotection. Although caffeine intake alters brain functional connectivity and multi-omics analyses indicate that caffeine intake modifies synaptic and metabolic processes, it is unclear how caffeine intake affects behavior, synaptic plasticity and its modulation by adenosine. We now report that male mice drinking caffeinated water (0.3 g/L) for 2 weeks were behaviorally indistinguishable (locomotion, mood, memory) from control mice (drinking water) and displayed superimposable synaptic plasticity (long-term potentiation) in different brain areas (hippocampus, prefrontal cortex, amygdala). Moreover, there was a general preservation of the efficiency of adenosine A1 and A2A receptors to control synaptic transmission and plasticity, although there was a tendency for lower levels of endogenous adenosine ensuring A1 receptor-mediated inhibition. In spite of similar behavioral and neurophysiological function, caffeine intake increased the energy charge and redox state of cortical synaptosomes. This increased metabolic competence likely involved a putative increase in the glycolytic rate in synapses and a prospective greater astrocyte–synapse lactate shuttling. It was concluded that caffeine intake does not trigger evident alterations of behavior or of synaptic plasticity but increases the metabolic competence of synapses, which might be related with the previously described better ability of animals consuming caffeine to cope with deleterious stimuli triggering brain dysfunction. [ABSTRACT FROM AUTHOR]

The hippocampus is a brain region involved in processing both memory and emotions, through a preferential involvement of the dorsal hippocampus (DH) and ventral hippocampus (VH), respectively. Adenosine A1 and A2A receptors (A1R and A2AR) control both mood and memory, but it is not known if there is a different adenosine modulation of synaptic plasticity along the hippocampal axis. Using adult, C57BL/6 male mice, we show that both A1R and A2AR were more abundant in DH compared with VH. However, recordings of field excitatory postsynaptic potentials at Schaffer collaterals‐CA1 pyramidal synapses revealed that A1R were equi‐effective to inhibit basal excitatory synaptic transmission in DH and VH, but endogenous A1R activation was more effective to depress the probability of release in VH. In contrast, the selective A2AR antagonist (SCH58261, 50 nM) controlled both long‐term potentiation (induced by a high frequency stimulation protocol) and long‐term depression (induced by a low frequency stimulation protocol) selectively in DH rather than VH, whereas the selective A1R antagonist (DPCPX, 100 nM) revealed a similar tonic inhibition of long‐term depression in DH and VH. These findings show a different control of synaptic plasticity by the adenosine modulation system in the dorsal and ventral poles of the hippocampus, which may underlie a different efficiency of the adenosine system to control mood and memory. [ABSTRACT FROM AUTHOR]

Cognitive impairments in Huntington's disease (HD) are attributed to a dysfunction of the cortico-striatal pathway and significantly affect the quality of life of the patients, but this has not been a therapeutic focus in HD to date. We postulated that adenosine A 2A receptors (A 2A R), located at pre- and post-synaptic elements of the cortico-striatal pathways, modulate striatal neurotransmission and synaptic plasticity and cognitive behaviors. To critically evaluate the ability of A 2A R inactivation to prevent cognitive deficits in early HD, we cross-bred A 2A R knockout (KO) mice with two R6/2 transgenic lines of HD (CAG120 and CAG240) to generate two double transgenic R6/2–CAG120–A 2A R KO and R6/2–CAG240–A 2A R KO mice and their corresponding wild-type (WT) littermates. Genetic inactivation of A 2A R prevented working memory deficits induced by R6/2–CAG120 at post-natal week 6 and by R6/2–CAG240 at post-natal month 2 and post-natal month 3, without modifying motor deficits. Similarly the A 2A R antagonist KW6002 selectively reverted working memory deficits in R6/2–CAG240 mice at post-natal month 3. The search for possible mechanisms indicated that the genetic inactivation of A 2A R did not affect ubiquitin-positive neuronal inclusions, astrogliosis or Thr-75 phosphorylation of DARPP-32 in the striatum. Importantly, A 2A R blockade preferentially controlled long-term depression at cortico-striatal synapses in R6/2–CAG240 at post-natal week 6. The reported reversal of working memory deficits in R6/2 mice by the genetic and pharmacological inactivation of A 2A R provides a proof-of-principle for A 2A R as novel targets to reverse cognitive deficits in HD, likely by controlling LTD deregulation. [ABSTRACT FROM AUTHOR]

The consumption of caffeine (an adenosine receptor antagonist) correlates inversely with depression and memory deterioration, and adenosine A2A receptor (A2AR) antagonists emerge as candidate therapeutic targets because they control aberrant synaptic plasticity and afford neuroprotection. Therefore we tested the ability of A2AR to control the behavioral, electrophysiological, and neurochemical modifications caused by chronic unpredictable stress (CUS), which alters hippocampal circuits, dampens mood and memory performance, and enhances susceptibility to depression. CUS for 3 wk in adult mice induced anxiogenic and helpless-like behavior and decreased memory performance. These behavioral changes were accompanied by synaptic alterations, typified by a decrease in synaptic plasticity and a reduced density of synaptic proteins (synaptosomal-associated protein 25, syntaxin, and vesicular glutamate transporter type 1), together with an increased density of A2AR in glutamatergic terminals in the hippocampus. Except for anxiety, for which results were mixed, CUS-induced behavioral and synaptic alterations were prevented by (i) caffeine (1 g/L in the drinking water, starting 3 wk before and continued throughout CUS); (ii) the selective A2AR antagonist KW6002 (3 mg/kg, p.o.); (iii) global A2AR deletion; and (iv) selective A2AR deletion in forebrain neurons. Notably, A2AR blockade was not only prophylactic but also therapeutically efficacious, because a 3-wk treatment with the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) reversed the mood and synaptic dysfunction caused by CUS. These results herald a key role for synaptic A2AR in the control of chronic stress-induced modifications and suggest A2AR as candidate targets to alleviate the consequences of chronic stress on brain function. [ABSTRACT FROM AUTHOR]

Adenosine A 2A receptors (A 2A R) overfunction causes synaptic and memory dysfunction in early Alzheimer's disease (AD). In a β-amyloid (Aβ 1-42)-based model of early AD, we now unraveled that this involves an increased synaptic release of ATP coupled to an increased density and activity of ecto-5′-nucleotidase (CD73)-mediated formation of adenosine selectively activating A 2A R. Thus, CD73 inhibition with α,β-methylene-ADP impaired long-term potentiation (LTP) in mouse hippocampal slices, which is occluded upon previous superfusion with the A 2A R antagonist SCH58261. Furthermore, α,β-methylene-ADP did not alter LTP amplitude in global A 2A R knockout (KO) and in forebrain neuron-selective A 2A R-KO mice, but inhibited LTP amplitude in astrocyte-selective A 2A R-KO mice; this shows that CD73-derived adenosine solely acts on neuronal A 2A R. In agreement with the concept that ATP is a danger signal in the brain, ATP release from nerve terminals is increased after intracerebroventricular Aβ 1-42 administration, together with CD73 and A 2A R upregulation in hippocampal synapses. Importantly, this increased CD73 activity is critically required for Aβ 1-42 to impair synaptic plasticity and memory since Aβ 1-42 -induced synaptic and memory deficits were eliminated in CD73-KO mice. These observations establish a key regulatory role of CD73 activity over neuronal A 2A R and imply CD73 as a novel target for modulation of early AD. • A 2A R-mediated control of LTP requires CD73-mediated catabolism into adenosine. • β-amyloid caused synaptic and memory dysfunction involving CD73/A 2A R upregulation. • A 2A R overfunction needs increased ATP release and CD73-convertion to adenosine. • CD73 is a key controller of A 2A R and a novel target to interfere with AD. [ABSTRACT FROM AUTHOR]

Extracellular ATP is a danger signal to the brain and contributes to neurodegeneration in animal models of Alzheimer's disease through its extracellular catabolism by CD73 to generate adenosine, bolstering the activation of adenosine A 2A receptors (A 2A R). Convulsive activity leads to increased ATP release, with the resulting morphological alterations being eliminated by A 2A R blockade. However, it is not known if upon convulsions there is a CD73-mediated coupling between ATP release and A 2A R overactivation, causing neurodegeneration. We now show that kainate-induced convulsions trigger a parallel increase of ATP release and of CD73 and A 2A R densities in synapses and astrocytes of the mouse hippocampus. Notably, the genetic deletion of CD73 attenuates neuronal degeneration but has no impact on astrocytic modifications in the hippocampus upon kainate-induced convulsions. Furthermore, kainate-induced convulsions cause a parallel deterioration of hippocampal long-term potentiation (LTP) and hippocampal-dependent memory performance, which is eliminated by knocking out CD73. This demonstrates the key role of the ATP release/CD73/A 2A R pathway to selectively control synaptic dysfunction and neurodegeneration following an acute brain insult, paving the way to consider CD73 as a new therapeutic target to prevent neuronal damage upon acute brain damage. • Convulsions lead to a sustained increase of ATP release from nerve terminals and astrocytes. • Convulsions upregulate synaptic and astrocytic CD73 and adenosine A 2A receptors. • CD73 knockout prevents convulsions-induced neurodegeneration and memory deficits. • ATP-CD73-A 2A receptor overfunction is a new pathway responsible for neuronal damage. [ABSTRACT FROM AUTHOR]

Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of function of the maternally inherited Ube3a neuronal protein, whose main features comprise severe intellectual disabilities and motor impairments. Previous studies with the Ube3a m−/p+ mouse model of AS revealed deficits in synaptic plasticity and memory. Since adenosine A 2A receptors (A 2A R) are powerful modulators of aberrant synaptic plasticity and A 2A R blockade prevents memory dysfunction in various brain diseases, we tested if A 2A R could control deficits of memory and hippocampal synaptic plasticity in AS. We observed that Ube3a m−/p+ mice were unable to resort to hippocampal-dependent search strategies when tested for learning and memory in the Morris water maze; this was associated with a decreased magnitude of long-term depression (LTD) in CA1 hippocampal circuits. There was an increased density of A 2A R in the hippocampus of Ube3a m−/p+ mice and their chronic treatment with the selective A 2A R antagonist SCH58261 (0.1 mg/kg/day, ip) restored both hippocampal-dependent learning strategies, as well as LTD deficits. Altogether, this study provides the first evidence of a role of A 2A R as a new prospective therapeutic target to manage learning deficits in AS. Unlabelled Image • Adenosine A 2A receptors are upregulated in the hippocampus of Ube3a m−/p+ mice. • Ube3a m−/p+ animals exhibit impaired hippocampal long-term depression. • Wild-type and Ube3a m−/p+ mice reveal distinct search patterns in a memory task. • Blockade of A 2A R restores Ube3a m−/p+ mice hippocampal long-term plasticity deficits. • Increased resource to hippocampus-dependent strategies is seen upon A 2A R blockade. [ABSTRACT FROM AUTHOR]