Inhibitory adenosine A1 receptors (A1Rs) are abundant throughout the brain, being present at pre-, post and non-synaptic sites to restrain neuronal excitability (e.g. Sebastião and Ribeiro, 2009). Excitatory actions of adenosine A2A receptors (A2Rs) in the hippocampus have been reported by us long ago but their scarce density in brain areas other than the striatum, namely in the hippocampus soon raised the hypothesis that the role of these receptors is fine tuning synapses rather than exerting a direct influence in synaptic transmission (see Sebastião and Ribeiro, 2009). Synapse fine tuning by A2ARs in the hippocampus has been recently extended to the tripartite synapse, including modulation of neurotransmitter transport in nerve endings and astrocytes as well as facilitation of responses to neurotransmitters and neuromodulators, with impact for synaptic plasticity, and I will refer to those studies. Activation of adenosine A2ARs enhances extrasynaptic AMPA receptor mediated responses in the hippocampus, by means of a PKA-dependent mechanism; this correlates with increases in the surface expression of GluR1 subunits phosphorylated at the Ser 845 residue, as well as with enhancements in synaptic transmission and plasticity, suggesting that A2ARs adjust the availability of the extrasynaptic pool GluR1-containing AMPA receptors for synaptic insertion and consequent reinforcement of synaptic strength (Dias et al., 2010). A distinct way used by A2ARs to reinforce synaptic strength is to gate plasticity-related BDNF actions (Diógenes et al., 2011), through a mechanism that involves translocation of BDNF TrkB receptors to lipid rafts (Assaife-Lopes et al., 2010). By allowing BDNF-induced inhibition of cholinergic inputs to inhibitory interneurones (Fernandes et al., 2008), A2ARs may also contribute to shape excitatory transmission in the hippocampus. A2ARs can interfere with the life-span of GABA at synapses, since they regulate the activity of GABA transporters (GATs). Indeed, GATs can be regulated by phosphorylation and we showed that GABA transport is facilitated by A2ARs in nerve endings (Cristovão-Ferreira et al., 2009). A2ARs facilitate transport of adenosine into nerve endings, limiting its availability to activate inhibitory adenosine A1 receptors (see Sebastião and Ribeiro, 2009), therefore contributing to a reduction of the adenosinergic inhibitory tonus at the synapses. Results obtained from alert-behaving mice provided evidence for a direct and endogenous role of A2ARs in the potentiation of hippocampal synaptic responses evoked during the acquisition of an associative learning task, since both synaptic potentiation and concomitant associative learning were prevented upon A2AR blockade (Fontinha et al., 2009). In summary, A2ARs, by enhancing the shut down of the inhibition by GABA and adenosine, as well as by directly facilitating glutamatergic AMPA receptor-mediated responses and by gating BDNF actions, exacerbate the excitatory tonus at synapses, therefore contributing in multiple complementary ways for synaptic reinforcement and plasticity.