Adenosine A_2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory

The consumption of caffeine modulates working and reference memory through the antagonism of adenosine A_2A receptors (A_2ARs) controlling synaptic plasticity processes in hippocampal excitatory synapses. Fear memory essentially involves plastic changes in amygdala circuits. However, it is unknown if A_2ARs in the amygdala regulate synaptic plasticity and fear memory. We report that A_2ARs 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 A_2ARs selectively in the basolateral complex of the amygdala, using a lentivirus with a silencing shRNA (small hairpin RNA targeting A_2AR (shA_2AR)), impaired fear acquisition as well as Pavlovian fear retrieval. This is probably associated with the upregulation and gain of function of A_2ARs in the amygdala after fear acquisition. The importance of A_2ARs to control fear memory was further confirmed by the ability of SCH58261 (0.1 mg/kg; A_2AR 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 A_2ARs control fear memory and the underlying process of synaptic plasticity in this brain region. This provides a neurophysiological basis for the association between A_2AR polymorphisms and phobia or panic attacks in humans and prompts a therapeutic interest in A_2ARs to manage fear-related pathologies.