Journal Article

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

Li, P, Cunha, R A, van Westen, G J P, Boyden, E S, Wang, Y, Chen, J-F, Zhou, X, Zhou, Y, PIJzerman, Ad, Gonçalves, N, Augusto, E, Li, Z, Wu, Z, Hou, X, Yoo, J-H, Li, W, Qu, J, Rial, D, Canas, P M, Tomé, A R, Payen, M-P

2015

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/51 / 14 / 14/34 / 42/109 / 631/378 / 82 / 96 / 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 / 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 / Mice / Mice, Inbred C57BL / Neurodegenerative diseases / Neurosciences / 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 memory / Synaptosomes - metabolism / Transfection / Transmembrane domains