title: Optogenetic activation of intracellular adenosine A2A receptor signaling in the hippocampus is sufficient to trigger CREB phosphorylation and impair memory.
abstract: 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 A2A receptors (A2ARs). To test if A2AR activation in the hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A2AR, we have developed a chimeric rhodopsin-A2AR protein (optoA2AR), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine-binding pockets) fused to the intracellular loop of A2AR to confer specific A2AR signaling. The specificity of the optoA2AR 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 A2AR. Supporting its physiological relevance, optoA2AR activation and the A2AR 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, optoA2AR activation triggered a preferential p-CREB signaling in the hippocampus and impaired spatial memory performance, while optoA2AR activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A2AR signaling in the hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A2AR signaling and functions depend on intracellular A2AR loops prompts the possibility of targeting the intracellular A2AR-interacting partners to selectively control different neuropsychiatric behaviors.
authors: Department of Neurology and Pharmacology, Boston University School of Medicine, Boston, MA, USA.|Molecular Biology Center, State Key Laboratory of Trauma, Burn, and Combined Injury, Research Institute of Surgery and Daping Hospital, Third Military Medical University, Chongqing, China.
authors: P
authors: P
authors: Li
authors: CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors: D
authors: D
authors: Rial
authors: CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors: P M
authors: PM
authors: Canas
authors: Department of Neurology and Pharmacology, Boston University School of Medicine, Boston, MA, USA.
authors: J-H
authors: JH
authors: Yoo
authors: Department of Neurology and Pharmacology, Boston University School of Medicine, Boston, MA, USA.|Molecular Biology Center, State Key Laboratory of Trauma, Burn, and Combined Injury, Research Institute of Surgery and Daping Hospital, Third Military Medical University, Chongqing, China.
authors: W
authors: W
authors: Li
authors: School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical College Wenzhou, Zhejiang, China.
authors: X
authors: X
authors: Zhou
authors: Department of Neurology and Pharmacology, Boston University School of Medicine, Boston, MA, USA.
authors: Y
authors: Y
authors: Wang
authors: Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors: G J P
authors: GJ
authors: van Westen
authors: Department of Neurology and Pharmacology, Boston University School of Medicine, Boston, MA, USA.
authors: M-P
authors: MP
authors: Payen
authors: Department of Neurology and Pharmacology, Boston University School of Medicine, Boston, MA, USA.|CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal.|Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors: E
authors: E
authors: Augusto
authors: CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors: N
authors: N
authors: Gonçalves
authors: CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors: A R
authors: AR
authors: Tomé
authors: School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical College Wenzhou, Zhejiang, China.
authors: Z
authors: Z
authors: Li
authors: School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical College Wenzhou, Zhejiang, China.
authors: Z
authors: Z
authors: Wu
authors: Department of Neurology and Pharmacology, Boston University School of Medicine, Boston, MA, USA.
authors: X
authors: X
authors: Hou
authors: Molecular Biology Center, State Key Laboratory of Trauma, Burn, and Combined Injury, Research Institute of Surgery and Daping Hospital, Third Military Medical University, Chongqing, China.
authors: Y
authors: Y
authors: Zhou
authors: A P
authors: AP
authors: IJzerman
authors: Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors: Ad
authors: A
authors: PIJzerman
authors: MIT Media Lab, Departments of Biological Engineering and Brain and Cognitive Sciences, MIT McGovern Institute, MIT, Cambridge, MA, USA.
authors: E S
authors: ES
authors: Boyden
authors: CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal.|Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors: R A
authors: RA
authors: Cunha
authors: School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical College Wenzhou, Zhejiang, China.
authors: J
authors: J
authors: Qu
authors: Department of Neurology and Pharmacology, Boston University School of Medicine, Boston, MA, USA.|School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical College Wenzhou, Zhejiang, China.
authors: J-F
authors: JF
authors: Chen
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008027:Light; D008569:Memory Disorders / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010627:Phenethylamines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D043683:Receptors, Adenosine A2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013574:Synaptosomes / Q000378:metabolism; D014162:Transfection
chemical_list: D058908:Adenosine A2 Receptor Agonists; D017362:Cyclic AMP Response Element-Binding Protein; D010627:Phenethylamines; D043683:Receptors, Adenosine A2; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine