Adenosine A2AReceptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory.
The consumption of caffeine modulates working and reference memory through the antagonism of adenosine A2Areceptors (A2ARs) controlling synaptic plasticity processes in hippocampal excitatory synapses. Fear memory essentially involves plastic changes in amygdala circuits. However, it is unknown if A2ARs in the amygdala regulate synaptic plasticity and fear memory. We report that A2ARs in the amygdala are enriched in synapses and located to glutamatergic synapses, where they selectively control synaptic plasticity rather than synaptic transmission at a major afferent pathway to the amygdala. Notably, the downregulation of A2ARs selectively in the basolateral complex of the amygdala, using a lentivirus with a silencing shRNA (small hairpin RNA targeting A2AR (shA2AR)), impaired fear acquisition as well as Pavlovian fear retrieval. This is probably associated with the upregulation and gain of function of A2ARs in the amygdala after fear acquisition. The importance of A2ARs to control fear memory was further confirmed by the ability of SCH58261 (0.1 mg/kg; A2AR antagonist), caffeine (5 mg/kg), but not DPCPX (0.5 mg/kg; A1R antagonist), treatment for 7 days before fear conditioning onwards, to attenuate the retrieval of context fear after 24-48 h and after 7-8 days. These results demonstrate that amygdala A2ARs control fear memory and the underlying process of synaptic plasticity in this brain region. This provides a neurophysiological basis for the association between A2AR polymorphisms and phobia or panic attacks in humans and prompts a therapeutic interest in A2ARs to manage fear-related pathologies.
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Ana Patrícia
AP
Simões
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Nuno J
0000-0001-5097-4231
NJ
Machado
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Nélio
N
Gonçalves
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Manuella P
MP
Kaster
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Ana T
AT
Simões
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Ana
A
Nunes
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Luís
L
Pereira de Almeida
McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
Ki Ann
KA
Goosens
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Daniel
D
Rial
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|FMUC-Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Rodrigo A
0000-0003-2550-6422
RA
Cunha
D000161:Acoustic Stimulation / Q000009:adverse effects; D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology / Q000633:toxicity; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology / Q000633:toxicity; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000187:drug effects / Q000502:physiology; D008124:Locomotion / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D008569:Memory Disorders / Q000139:chemically induced; D051379:Mice; D008810:Mice, Inbred C57BL; D011743:Pyrimidines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; D014970:Xanthines; C097270:ZM 241385; C051360:1,3-dipropyl-8-cyclopentylxanthine