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

Molecular Psychiatry volume 20, pages 1339–1349 (2015)Cite this article

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An Erratum to this article was published on 24 March 2015

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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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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Authors and Affiliations

  1. Department of Neurology and Pharmacology, Boston University School of Medicine, Boston, MA, USA

    P Li, J-H Yoo, W Li, Y Wang, M-P Payen, E Augusto, X Hou & J-F Chen

  2. 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

    P Li, W Li & Y Zhou

  3. CNC – Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal

    D Rial, P M Canas, E Augusto, N Gonçalves, A R Tomé & R A Cunha

  4. School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical College Wenzhou, Zhejiang, China

    X Zhou, Z Li, Z Wu, J Qu & J-F Chen

  5. Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands

    G J P van Westen & Ad PIJzerman

  6. Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    E Augusto & R A Cunha

  7. Departments of Biological Engineering and Brain and Cognitive Sciences, MIT Media Lab, MIT McGovern Institute, MIT, Cambridge, MA, USA

    E S Boyden

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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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