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.
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References
van Boxtel MP, Schmitt JA, Bosma H, Jolles J . The effects of habitual caffeine use on cognitive change: a longitudinal perspective. Pharmacol Biochem Behav 2003; 75: 921–927.
Hameleers PA, Van Boxtel MP, Hogervorst E, Riedel WJ, Houx PJ, Buntinx F, et al. Habitual caffeine consumption and its relation to memory, attention, planning capacity and psychomotor performance across multiple age groups. Hum Psychopharmacol 2000; 15: 573–581.
Lindsay J, Laurin D, Verreault R, Hebert R, Helliwell B, Hill GB, et al. Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol 2002; 156: 445–453.
van Gelder BM, Buijsse B, Tijhuis M, Kalmijn S, Giampaoli S, Nissinen A, et al. Coffee consumption is inversely associated with cognitive decline in elderly European men: the FINE Study. Eur J Clin Nutr 2007; 61: 226–232.
Ritchie K, Carriere I, de Mendonca A, Portet F, Dartigues JF, Rouaud O et al. The neuroprotective effects of caffeine: a prospective population study (the Three City Study). Neurology 2007; 69: 536–545.
Gelber RP, Petrovitch H, Masaki KH, Ross GW, White LR . Coffee intake in midlife and risk of dementia and its neuropathologic correlates. J Alzheimers Dis 2011; 23: 607–615.
Eskelinen MH, Ngandu T, Tuomilehto J, Soininen H, Kivipelto M . Midlife coffee and tea drinking and the risk of late-life dementia: a population-based CAIDE study. J Alzheimers Dis 2009; 16: 85–91.
Dall'Igna OP, Fett P, Gomes MW, Souza DO, Cunha RA, Lara DR . Caffeine and adenosine A2a receptor antagonists prevent beta-amyloid (25–35)-induced cognitive deficits in mice. Exp Neurol 2007; 203: 241–245.
Cunha GM, Canas PM, Melo CS, Hockemeyer J, Muller CE, Oliveira CR, et al. Adenosine A2A receptor blockade prevents memory dysfunction caused by beta-amyloid peptides but not by scopolamine or MK-801. Exp Neurol 2008; 210: 776–781.
Arendash GW, Schleif W, Rezai-Zadeh K, Jackson EK, Zacharia LC, Cracchiolo JR, et al. Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production. Neuroscience 2006; 142: 941–952.
Espinosa J, Rocha A, Nunes F, Costa MS, Schein V, Kazlauckas V, et al. Caffeine consumption prevents memory impairment, neuronal damage, and adenosine A2A receptors upregulation in the hippocampus of a rat model of sporadic dementia. J Alzheimers Dis 2013; 34: 509–518.
Cognato GP, Agostinho PM, Hockemeyer J, Muller CE, Souza DO, Cunha RA . Caffeine and an adenosine A2A receptor antagonist prevent memory impairment and synaptotoxicity in adult rats triggered by a convulsive episode in early life. J Neurochem 2010; 112: 453–462.
Duarte JM, Agostinho PM, Carvalho RA, Cunha RA . Caffeine consumption prevents diabetes-induced memory impairment and synaptotoxicity in the hippocampus of NONcZNO10/LTJ mice. PLoS One 2012; 7: e21899.
Canas PM, Porciuncula LO, Cunha GM, Silva CG, Machado NJ, Oliveira JM, et al. Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway. J Neurosci 2009; 29: 14741–14751.
Prediger RD, Batista LC, Takahashi RN . Caffeine reverses age-related deficits in olfactory discrimination and social recognition memory in rats. Involvement of adenosine A1 and A2A receptors. Neurobiol Aging 2005; 26: 957–964.
Zhou SJ, Zhu ME, Shu D, Du XP, Song XH, Wang XT, et al. Preferential enhancement of working memory in mice lacking adenosine A2A receptors. Brain Res 2009; 1303: 74–83.
Wei CJ, Singer P, Coelho J, Boison D, Feldon J, Yee BK, et al. Selective inactivation of adenosine A2A receptors in striatal neurons enhances working memory and reversal learning. Learn Mem 2011; 18: 459–474.
Yu C, Gupta J, Chen JF, Yin HH . Genetic deletion of A2A adenosine receptors in the striatum selectively impairs habit formation. J Neurosci 2009; 29: 15100–15103.
Wei CJ, Augusto E, Gomes CA, Singer P, Wang Y, Boison D et al. Regulation of fear responses by striatal and extrastriatal adenosine A2A receptors in forebrain. Biol Psychiatry 2013; 75: 855–863.
Kadowaki Horita T, Kobayashi M, Mori A, Jenner P, Kanda T . Effects of the adenosine A2A antagonist istradefylline on cognitive performance in rats with a 6-OHDA lesion in prefrontal cortex. Psychopharmacology (Berl) 2013; 230: 345–352.
Cunha RA, Almeida T, Ribeiro JA . Parallel modification of adenosine extracellula r metabolism and modulatory action in the hippocampus of aged rats. J Neurochem 2001; 76: 372–382.
Chen JF, Eltzschig HK, Fredholm BB . Adenosine receptors as drug targets—what are the challenges? Nat Rev Drug Discov 2013; 12: 265–286.
Cunha RA, Agostinho PM . Chronic caffeine consumption prevents memory disturbance in different animal models of memory decline. J Alzheimers Dis 2010; 20: S95–116.
Chen JF, Sonsalla PK, Pedata F, Melani A, Domenici MR, Popoli P, et al. Adenosine A2A receptors and brain injury: broad spectrum of neuroprotection, multifaceted actions and ‘fine tuning’ modulation. Prog Neurobiol 2007; 83: 310–331.
Fredholm BB, Chern Y, Franco R, Sitkovsky M . Aspects of the general biology of adenosine A2A signaling. Prog Neurobiol 2007; 83: 263–276.
Shen HY, Canas PM, Garcia-Sanz P, Lan JQ, Boison D, Moratalla R, et al. Adenosine A2A receptors in striatal glutamatergic terminals and GABAergic neurons oppositely modulate psychostimulant action and DARPP-32 phosphorylation. PLoS One 2013; 8: e80902.
Shen HY, Coelho JE, Ohtsuka N, Canas PM, Day YJ, Huang QY, et al. A critical role of the adenosine A2A receptor in extrastriatal neurons in modulating psychomotor activity as revealed by opposite phenotypes of striatum and forebrain A2A receptor knock-outs. J Neurosci 2008; 28: 2970–2975.
Ciruela F, Casado V, Rodrigues RJ, Lujan R, Burgueno J, Canals M, et al. Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1–A2A receptor heteromers. J Neurosci 2006; 26: 2080–2087.
Keuerleber S, Gsandtner I, Freissmuth M . From cradle to twilight: the carboxyl terminus directs the fate of the A2A-adenosine receptor. Biochim Biophys Acta 2011; 1808: 1350–1357.
Mundell S, Kelly E . Adenosine receptor desensitization and trafficking. Biochim Biophys Acta 2011; 1808: 1319–1328.
Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K . Millisecond-timescale genetically targeted optical control of neural activity. Nat Neurosci 2005; 8: 1263–1268.
Chen JF, Huang Z, Ma J, Zhu J, Moratalla R, Standaert D et al. A(2A) adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice. J Neurosci 1999; 19: 9192–9200.
Costenla AR, Diogenes MJ, Canas PM, Rodrigues RJ, Nogueira C, Maroco J, et al. Enhanced role of adenosine A(2A) receptors in the modulation of LTP in the rat hippocampus upon ageing. The European Journal of Neuroscience 2011; 34: 12–21.
Cognato GP, Agostinho PM, Hockemeyer J, Muller CE, Souza DO, Cunha RA, et al. Caffeine and an adenosine A(2A) receptor antagonist prevent memory impairment and synaptotoxicity in adult rats triggered by a convulsive episode in early life. Journal of Neurochemistry 2010; 112: 453–462.
Rebola N, Canas PM, Oliveira CR, Cunha RA . Different synaptic and subsynaptic localization of adenosine A2A receptors in the hippocampus and striatum of the rat. Neuroscience 2005; 132: 893–903.
Rebola N, Rodrigues RJ, Lopes LV, Richardson PJ, Oliveira CR, Cunha RA . Adenosine A1 and A2A receptors are co-expressed in pyramidal neurons and co-localized in glutamatergic nerve terminals of the rat hippocampus. Neuroscience 2005; 133: 79–83.
Rodrigues RJ, Canas PM, Oliveira CR, Cunha RA . Modification of adenosine modulation of acetylcholine release in the hippocampus of aged rats. Neurobiology of aging 2008; 29: 1597–1601.
Borroto-Escuela DO, Romero-Fernandez W, Tarakanov AO, Gomez-Soler M, Corrales F, Marcellino D, et al. Characterization of the A2AR-D2R interface: focus on the role of the C-terminal tail and the transmembrane helices. Biochem Biophys Res Commun 2010; 402: 801–807.
Viosca J, Malleret G, Bourtchouladze R, Benito E, Vronskava S, Kandel ER, et al. Chronic enhancement of CREB activity in the hippocampus interferes with the retrieval of spatial information. Learn Mem 2009; 16: 198–209.
Britt JP, Benaliouad F, McDevitt RA, Stuber GD, Wise RA, Bonci A . Synaptic and behavioral profile of multiple glutamatergic inputs to the nucleus accumbens. Neuron 2012; 76: 790–803.
Chuhma N, Tanaka KF, Hen R, Rayport S . Functional connectome of the striatal medium spiny neuron. J Neurosci 2011; 31: 1183–1192.
Kenakin T, Christopoulos A . Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nat Rev Drug Discov 2013; 12: 205–216.
Gerfen CR, Engber TM, Mahan LC, Susel Z, Chase TN, Monsma FJ Jr, et al. D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 1990; 250: 1429–1432.
Hauber W, Munkle M . Motor depressant effects mediated by dopamine D2 and adenosine A2A receptors in the nucleus accumbens and the caudate–putamen. Eur J Pharmacol 1997; 323: 127–131.
Barraco RA, Martens KA, Parizon M, Normile HJ . Role of adenosine A2a receptors in the nucleus accumbens. Prog Neuropsychopharmacol Biol Psychiatry 1994; 18: 545–553.
Svenningsson P, Le Moine C, Fisone G, Fredholm BB . Distribution, biochemistry and function of striatal adenosine A2A receptors. Prog Neurobiol 1999; 59: 355–396.
Canas PM, Duarte JM, Rodrigues RJ, Kofalvi A, Cunha RA . Modification upon aging of the density of presynaptic modulation systems in the hippocampus. Neurobiol Aging 2009; 30: 1877–1884.
Albasanz JL, Perez S, Barrachina M, Ferrer I, Martín M . Up-regulation of adenosine receptors in the frontal cortex in Alzheimer's disease. Brain Pathol 2008; 18: 211–219.
Benito E, Barco A . CREB's control of intrinsic and synaptic plasticity: implications for CREB-dependent memory models. Trends Neurosci 2010; 33: 230–240.
Bockaert J, Perroy J, Bécamel C, Marin P, Fagni L . GPCR interacting proteins (GIPs) in the nervous system: roles in physiology and pathologies. Annu Rev Pharmacol Toxicol 2010; 50: 89–109.
Gsandtner I, Charalambous C, Stefan E, Ogris E, Freissmuth M, Zezula J . Heterotrimeric G protein-independent signaling of a G protein-coupled receptor. Direct binding of ARNO/cytohesin-2 to the carboxyl terminus of the A2A adenosine receptor is necessary for sustained activation of the ERK/MAP kinase pathway. J Biol Chem 2005; 280: 31898–31905.
Rajagopal R, Chen ZY, Lee FS, Chao MV . Transactivation of Trk neurotrophin receptors by G-protein-coupled receptor ligands occurs on intracellular membranes. J Neurosci 2004; 24: 6650–6658.
Flajolet M, Wang Z, Futter M, Shen W, Nuangchamnong N, Bendor J, et al. FGF acts as a co-transmitter through adenosine A2A receptor to regulate synaptic plasticity. Nat Neurosci 2008; 11: 1402–1409.
Sun CN, Cheng HC, Chou JL, Lee SY, Lin YW, Lai HL, et al. Rescue of p53 blockage by the A2A adenosine receptor via a novel interacting protein, translin-associated protein X. Mol Pharmacol 2006; 70: 454–466.
Sun CN, Chuang HC, Wang JY, Chen SY, Cheng YY, Lee CF, et al. The A2A adenosine receptor rescues neuritogenesis impaired by p53 blockage via KIF2A, a kinesin family member. Dev Neurobiol 2010; 70: 604–621.
Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd JW, et al. Treatment of ischemic brain damage by perturbing NMDA receptor–PSD-95 protein interactions. Science 2002; 298: 846–850.
Cook DJ, Teves L, Tymianski M . Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature 2012; 483: 213–217.
Ji SP, Zhang Y, Van Cleemput J, Jiang W, Liao M, Li L, et al. Disruption of PTEN coupling with 5-HT2C receptors suppresses behavioral responses induced by drugs of abuse. Nat Med 2006; 12: 324–329.
Wei CJ, Li W, Chen JF . Normal and abnormal functions of adenosine receptors in the central nervous system revealed by genetic knockout studies. Biochim Biophys Acta 2011; 1808: 1358–1379.
Gomes CV, Kaster MP, Tome AR, Agostinho PM, Cunha RA . Adenosine receptors and brain diseases: neuroprotection and neurodegeneration. Biochim Biophys Acta 2011; 1808: 1380–1399.
Dellu F, Fauchey V, Le Moal M, Simon H . Extension of a new two-trial memory task in the rat: influence of environmental context on recognition processes. Neurobiol Learn Mem 1997; 67: 112–120.
Acknowledgements
This work was supported by NIH (NS041083-11, NS073947), the MacDonald Foundation for Huntington’s Research, Defense Advanced Research Projects Agency (Grant W911NF-10-1-0059) and Brain and Behavior Research Foundation (NARSAD Independent Investigator Grant). This study was also sponsored by the National Basic Research Program of China (973 Project, 2011CB504602), the Start-up Fund from Wenzhou Medical University (No. 89211010 and No. 89212012), the Zhejiang Provincial Special Funds (No. 604161241), the Special Fund for Building Key National Clinical Resource (Key Laboratory of Vision Science, Ministry of Health, No. 601041241), the Central Government Special Fund for Local Universities' Development (No. 474091314) and by special BUSM research fund DTD 4-30-14. We thank João Peça (CNC) for providing the calibrated light source for the slice experiments.
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Li, P., Rial, D., Canas, P. et al. Optogenetic activation of intracellular adenosine A2A receptor signaling in the hippocampus is sufficient to trigger CREB phosphorylation and impair memory. Mol Psychiatry 20, 1339–1349 (2015). https://doi.org/10.1038/mp.2014.182
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DOI: https://doi.org/10.1038/mp.2014.182
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