Optogenetic activation of intracellular adenosine A2A receptor signaling in the hippocampus is sufficient to trigger CREB phosphorylation and impair memory

• Published in: Molecular psychiatry Vol. 20; no. 11; pp. 1339 - 1349
• Main Authors: Li, P, Rial, D, Canas, P M, Yoo, J-H, Li, W, Zhou, X, Wang, Y, van Westen, G J P, Payen, M-P, Augusto, E, Gonçalves, N, Tomé, A R, Li, Z, Wu, Z, Hou, X, Zhou, Y, PIJzerman, Ad, Boyden, E S, Cunha, R A, Qu, J, Chen, J-F
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-11-2015; Nature Publishing Group
• Subjects: 13/51; 14; 14/34; 42/109; 631/378; 82; 96; Activation; Adenosine; Adenosine - analogs & derivatives; Adenosine - pharmacology; Adenosine A2 Receptor Agonists - pharmacology; Adenosine A2A receptors; Aging; Alzheimer's disease; Animal cognition; Animals; Behavioral Sciences; Biological Psychology; Brain research; c-Fos protein; Caffeine; Cell Membrane - metabolism; Cognitive ability; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - metabolism; Cyclic GMP; Disease Models, Animal; Exploratory Behavior - physiology; HEK293 Cells; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Humans; In Vitro Techniques; Intracellular; Intracellular signalling; Kinases; Light; Light effects; Locomotor activity; Long-term potentiation; MAP kinase; Medicine; Medicine & Public Health; Memory; Memory Disorders - drug therapy; Memory Disorders - genetics; Memory Disorders - pathology; Memory tasks; Mice; Mice, Inbred C57BL; Neurodegenerative diseases; Neurosciences; Nuclei (cytology); Nucleus accumbens; original-article; Pharmacotherapy; Phenethylamines - pharmacology; Phosphorylation; Phosphorylation - drug effects; Phosphorylation - genetics; Physiology; Point mutation; Protein kinase; Proteins; Psychiatry; Receptors, Adenosine A2 - genetics; Receptors, Adenosine A2 - metabolism; Rhodopsin; Signal Transduction - drug effects; Signal Transduction - genetics; Spatial analysis; Spatial memory; Synaptosomes - metabolism; Transfection; Transmembrane domains; United States > US; Portugal; China
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2014.182

Human and animal studies have converged to suggest that caffeine consumption prevents memory deficits in aging and Alzheimer’s disease through the antagonism of adenosine A
2A
receptors (A
2A
Rs). To test if A
2A
R activation in the hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A
2A
R, we have developed a chimeric rhodopsin-A
2A
R protein (
optoA
2A
R
), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine-binding pockets) fused to the intracellular loop of A
2A
R to confer specific A
2A
R signaling. The specificity of the
optoA
2A
R
signaling was confirmed by light-induced selective enhancement of cAMP and phospho-mitogen-activated protein kinase (p-MAPK) (but not cGMP) levels in human embryonic kidney 293 (HEK293) cells, which was abolished by a point mutation at the C terminal of A
2A
R. Supporting its physiological relevance,
optoA
2A
R
activation and the A
2A
R agonist CGS21680 produced similar activation of cAMP and p-MAPK signaling in HEK293 cells, of p-MAPK in the nucleus accumbens and of c-Fos/phosphorylated-CREB (p-CREB) in the hippocampus, and similarly enhanced long-term potentiation in the hippocampus. Remarkably,
optoA
2A
R
activation triggered a preferential p-CREB signaling in the hippocampus and impaired spatial memory performance, while
optoA
2A
R
activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A
2A
R signaling in the hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A
2A
R signaling and functions depend on intracellular A
2A
R loops prompts the possibility of targeting the intracellular A
2A
R-interacting partners to selectively control different neuropsychiatric behaviors.