Optogenetic activation of intracellular adenosine A2A receptor signaling in the hippocampus is sufficient to trigger CREB phosphorylation and impair memory
Mol Psychiatry. 2015-02-17; 20(11): 1339-1349
DOI: 10.1038/mp.2014.182
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Li P(1)(2), Rial D(3), Canas PM(3), Yoo JH(1), Li W(1)(2), Zhou X(4), Wang Y(1),
van Westen GJ(5), Payen MP(1), Augusto E(1)(3)(6), Gonçalves N(3), Tomé AR(3),
Li Z(4), Wu Z(4), Hou X(1), Zhou Y(2), IJzerman AP, Boyden ES(7), Cunha
RA(3)(6), Qu J(4), Chen JF(1)(4).
Author information:
(1)Department of Neurology and Pharmacology, Boston University School of
Medicine, Boston, MA, USA.
(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.
(3)CNC – Center for Neurosciences and Cell Biology, University of Coimbra,
Coimbra, Portugal.
(4)School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical
College Wenzhou, Zhejiang, China.
(5)Leiden Academic Centre for Drug Research, Leiden University, Leiden, The
Netherlands.
(6)Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
(7)MIT Media Lab, Departments of Biological Engineering and Brain and Cognitive
Sciences, MIT McGovern Institute, MIT, Cambridge, MA, USA.
Erratum in
Mol Psychiatry. 2015 Nov;20(11):1481. PIJzerman, Ad [Corrected to IJzerman,
AP].
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