Adenosine A2b receptors control A1 receptor-mediated inhibition of synaptic transmission in the mouse hippocampus

Adenosine is a neuromodulator mostly acting through A(1) (inhibitory) and A(2A) (excitatory) receptors in the brain. A(2B) receptors (A(2B)R) are G(s/q)-protein-coupled receptors with low expression in the brain. As A(2B)R function is largely unknown, we have now explored their role in the mouse hippocampus. We performed electrophysiological extracellular recordings in mouse hippocampal slices, and immunological analysis of nerve terminals and glutamate release in hippocampal slices and synaptosomes. Additionally, A(2B)R-knockout (A(2B)R-KO) and C57/BL6 mice were submitted to a behavioural test battery (open field, elevated plus-maze, Y-maze). The A(2B)R agonist BAY60-6583 (300nm) decreased the paired-pulse stimulation ratio, an effect prevented by the A(2B)R antagonist MRS1754 (200 nM) and abrogated in A(2B)R-KO mice. Accordingly, A(2B)R immunoreactivity was present in 73 +/- 5% of glutamatergic nerve terminals, i.e. those immunopositive for vesicular glutamate transporters. Furthermore, BAY60-6583 attenuated the A(1)R control of synaptic transmission, both the A(1)R inhibition caused by 2-chloroadenosine (0.1-1m) and the disinhibition caused by the A(1)R antagonist DPCPX (100nm), both effects prevented by MRS1754 and abrogated in A(2B)R-KO mice. BAY60-6583 decreased glutamate release in slices and also attenuated the A(1)R inhibition (CPA 100nm). A(2B)R-KO mice displayed a modified exploratory behaviour with an increased time in the central areas of the open field, elevated plus-maze and the Y-maze and no alteration of locomotion, anxiety or working memory. We conclude that A(2B)R are present in hippocampal glutamatergic terminals where they counteract the predominant A(1)R-mediated inhibition of synaptic transmission, impacting on exploratory behaviour.