Adenosine A2A 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(2A)Rs) controlling synaptic plasticity processes in hippocampal excitatory synapses. Fear memory essentially involves plastic changes in amygdala circuits. However, it is unknown if A(2A)Rs in the amygdala regulate synaptic plasticity and fear memory. We report that A(2A)Rs 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(2A)Rs selectively in the basolateral complex of the amygdala, using a lentivirus with a silencing shRNA (small hairpin RNA targeting A(2A)R (shA(2A)R)), impaired fear acquisition as well as Pavlovian fear retrieval. This is probably associated with the upregulation and gain of function of A(2A)Rs in the amygdala after fear acquisition. The importance of A(2A)Rs to control fear memory was further confirmed by the ability of SCH58261 (0.1 mg/kg; A(2A)R antagonist), caffeine (5 mg/kg), but not DPCPX (0.5 mg/kg; A(1)R 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(2A)Rs control fear memory and the underlying process of synaptic plasticity in this brain region. This provides a neurophysiological basis for the association between A(2A)R polymorphisms and phobia or panic attacks in humans and prompts a therapeutic interest in A(2A)Rs to manage fear-related pathologies.