Retrograde adenosine/A2A receptor signaling mediates presynaptic hippocampal LTP and facilitates epileptic seizures

A long-term change in neurotransmitter release is a widely expressed mechanism controlling neural circuits in the mammalian brain. This presynaptic plasticity is commonly mediated by retrograde signaling whereby a messenger released from the postsynaptic neuron upon activity modifies neurotransmitter release in a long-term manner by targeting a presynaptic receptor. In the dentate gyrus (DG), the main input area of the hippocampus, granule cells (GCs) and mossy cells (MCs) form a recurrent excitatory circuit that is critically involved in DG function and epilepsy. Here, we identified adenosine/A2A receptor (A2AR) as a novel retrograde signaling system that mediates presynaptic long-term potentiation (LTP) at MC-GC synapses. Using an adenosine sensor, we found that neuronal activity triggered phasic, postsynaptic TrkB-dependent release of adenosine. Additionally, epileptic seizures released adenosine in vivo, while removing A2ARs from DG decreased seizure susceptibility. Thus, adenosine/A2AR retrograde signaling mediates presynaptic LTP that may contribute to DG-dependent learning and promote epilepsy.

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Purinergic P2 receptors trigger adenosine release leading to adenosine A2A receptor activation and facilitation of long-term potentiation in rat hippocampal slices

Neuroscience ◽

10.1016/s0306-4522(03)00523-2 ◽

2003 ◽

Vol 122 (1) ◽

pp. 111-121 ◽

Cited By ~ 31

Author(s):

T. Almeida ◽

R.J. Rodrigues ◽

A. de Mendonça ◽

J.A. Ribeiro ◽

R.A. Cunha

Keyword(s):

Hippocampal Slices ◽

Long Term Potentiation ◽

Receptor Activation ◽

P2 Receptors ◽

Adenosine A2a Receptor ◽

Adenosine Release ◽

Term Potentiation ◽

A2a Receptor ◽

Adenosine A2a

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Inactivation of adenosine A2A receptor impairs long term potentiation in the accumbens nucleus without altering basal synaptic transmission

Neuroscience ◽

10.1016/s0306-4522(01)00372-4 ◽

2001 ◽

Vol 107 (3) ◽

pp. 455-464 ◽

Cited By ~ 77

Author(s):

P d’Alcantara ◽

C Ledent ◽

S Swillens ◽

S.N Schiffmann

Keyword(s):

Synaptic Transmission ◽

Long Term Potentiation ◽

Adenosine A2a Receptor ◽

Term Potentiation ◽

A2a Receptor ◽

Accumbens Nucleus ◽

Adenosine A2a ◽

Basal Synaptic Transmission

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Enhancement of long-term potentiation by brain-derived neurotrophic factor requires adenosine A2A receptor activation by endogenous adenosine

Neuropharmacology ◽

10.1016/j.neuropharm.2008.01.011 ◽

2008 ◽

Vol 54 (6) ◽

pp. 924-933 ◽

Cited By ~ 77

Author(s):

B.M. Fontinha ◽

M.J. Diógenes ◽

J.A. Ribeiro ◽

A.M. Sebastião

Keyword(s):

Neurotrophic Factor ◽

Long Term Potentiation ◽

Brain Derived Neurotrophic Factor ◽

Receptor Activation ◽

Adenosine A2a Receptor ◽

Endogenous Adenosine ◽

Term Potentiation ◽

A2a Receptor ◽

Adenosine A2a

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Adenosine A2A receptor signaling promotes FoxO associated autophagy in chondrocytes

Scientific Reports ◽

10.1038/s41598-020-80244-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Benjamin Friedman ◽

Carmen Corciulo ◽

Cristina M. Castro ◽

Bruce N. Cronstein

Keyword(s):

Cell Line ◽

Metabolic Stress ◽

Human Cell Line ◽

Adenosine A2a Receptor ◽

Autophagic Flux ◽

A2a Receptor ◽

Adenosine A2a ◽

A2ar Agonist

AbstractAutophagy, a homeostatic pathway upregulated during cellular stress, is decreased in osteoarthritic chondrocytes and this reduction in autophagy is thought to contribute to the development and progression of osteoarthritis (OA). The adenosine A2A receptor (A2AR) is a potent anti-inflammatory receptor and deficiency of this receptor leads to the development of OA in mice. Moreover, treatment using liposomally conjugated adenosine or a specific A2AR agonist improved joint scores significantly in both rats with post-traumatic OA (PTOA) and mice subjected to a high fat diet obesity induced OA. Importantly, A2AR ligation is beneficial for mitochondrial health and metabolism in vitro in primary and the TC28a2 human cell line. An additional set of metabolic, stress-responsive, and homeostatic mediators include the Forkhead box O transcription factors (FoxOs). Data has shown that mouse FoxO knockouts develop early OA with reduced cartilage autophagy, indicating that FoxO-induced homeostasis is important for articular cartilage. Given the apparent similarities between A2AR and FoxO signaling, we tested the hypothesis that A2AR stimulation improves cartilage function through activation of the FoxO proteins leading to increased autophagy in chondrocytes. We analyzed the signaling pathway in the human TC28a2 cell line and corroborated these findings in vivo in a metabolically relevant obesity-induced OA mouse model. We found that A2AR stimulation increases activation and nuclear localization of FoxO1 and FoxO3, promotes an increase in autophagic flux, improves metabolic function in chondrocytes, and reduces markers of apoptosis in vitro and reduced apoptosis by TUNEL assay in vivo. A2AR ligation additionally enhances in vivo activation of FoxO1 and FoxO3 with evidence of enhanced autophagic flux upon injection of the liposome-associated A2AR agonist in a mouse obesity-induced OA model. These findings offer further evidence that A2AR may be an excellent target for promoting chondrocyte and cartilage homeostasis.

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Development of 18F-Labeled Radiotracers for PET Imaging of the Adenosine A2A Receptor: Synthesis, Radiolabeling and Preliminary Biological Evaluation

International Journal of Molecular Sciences ◽

10.3390/ijms22052285 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2285

Author(s):

Thu Hang Lai ◽

Susann Schröder ◽

Magali Toussaint ◽

Sladjana Dukić-Stefanović ◽

Mathias Kranz ◽

...

Keyword(s):

Specific Binding ◽

Brain Slices ◽

Total Activity ◽

Biological Evaluation ◽

Adenosine A2a Receptor ◽

Positron Emission ◽

A2a Receptor ◽

Adenosine A2a

The adenosine A2A receptor (A2AR) represents a potential therapeutic target for neurodegenerative diseases. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor changes of receptor density and/or occupancy during the A2AR-tailored therapy, we designed a library of fluorinated analogs based on a recently published lead compound (PPY). Among those, the highly affine 4-fluorobenzyl derivate (PPY1; Ki(hA2AR) = 5.3 nM) and the 2-fluorobenzyl derivate (PPY2; Ki(hA2AR) = 2.1 nM) were chosen for 18F-labeling via an alcohol-enhanced copper-mediated procedure starting from the corresponding boronic acid pinacol ester precursors. Investigations of the metabolic stability of [18F]PPY1 and [18F]PPY2 in CD-1 mice by radio-HPLC analysis revealed parent fractions of more than 76% of total activity in the brain. Specific binding of [18F]PPY2 on mice brain slices was demonstrated by in vitro autoradiography. In vivo PET/magnetic resonance imaging (MRI) studies in CD-1 mice revealed a reasonable high initial brain uptake for both radiotracers, followed by a fast clearance.

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The Diameter of Retinal Arterioles Is Unaffected by Intravascular Administration of the Adenosine A2A Receptor Agonist Regadenoson in Normal Persons

Biomedicine Hub ◽

10.1159/000500563 ◽

2019 ◽

Vol 4 (2) ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Anna Dons-Jensen ◽

Line Petersen ◽

Hans-Erik Bøtker ◽

Toke Bek

Keyword(s):

Intravenous Administration ◽

Receptor Agonist ◽

Adenosine A2a Receptor ◽

Retinal Vessels ◽

Adenosine Receptor Agonists ◽

Retinal Arterioles ◽

A2a Receptor ◽

Adenosine A2a

Background: The neurotransmitter adenosine has been proposed to be involved in the pathogenesis of diabetic retinopathy, which may be due to the vasoactive properties of the compound. Previous studies have shown that adenosine can affect the tone of retinal arterioles in vitro to induce dilatation mediated by A2A and A2Breceptors and constriction mediated by A1 and A3 receptors. Purpose: To investigate effects of intravenous administration of the adenosine A2A receptor agonist regadenoson on the diameter of retinal vessels in vivo. Method: The diameter responses of larger retinal arterioles and venules were evaluated using the dynamic vessel analyser in 20 normal persons (age 22–31 years) after intravenous administration of the adenosine A2A receptor agonist regadenoson during exposure to systemic normoxia and hypoxia. Results: The diameter of retinal arterioles and venules increased significantly during stimulation with flickering light (p < 0.0001). Regadenoson reduced the flicker-induced dilatation of venules during normoxia (p = 0.0006), but otherwise had no effect on vessel diameters (p > 0.08 for all comparisons). Conclusions:Intravenous administration of the adenosine A2A receptor agonist regadenoson had no significant effect on the diameter of retinal arterioles. Future studies should investigate differential effects of intra- and extravascular administration of adenosine receptor agonists on retinal vessels.

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