Adenosine A_2b receptors control A₁ receptor‐mediated inhibition of synaptic transmission in the mouse hippocampus

Abstract

Adenosine is a neuromodulator mostly acting through A1 (inhibitory) and A2A (excitatory) receptors in the brain. A2B 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 (300 nM) decreased the paired-pulse stimulation ratio, an effect prevented by the A(2B)R antagonist MRS 1754 (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, BAY 60-6583 attenuated the A(1)R control of synaptic transmission, both the A(1)R inhibition caused by 2-chloroadenosine (0.1-1 μM) and the disinhibition caused by the A(1)R antagonist DPCPX (100 nM), both effects prevented by MRS 1754 and abrogated in A(2B)R-KO mice. BAY 60-6583 decreased glutamate release in slices and also attenuated the A(1)R inhibition (CPA 100 nM). 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.

Tremorolytic effect of 5′‐chloro‐5′‐deoxy‐(±)‐ENBA, a potent and selective adenosine A1 receptor agonist, evaluated in the harmaline‐induced model in rats

“…In fact, harmaline has been reported to activate 5′‐nucleotidase (an intracellular enzyme which hydrolyzes 5′‐AMP to adenosine), suggesting an increase in adenosine level and release. Adenosine A 1 receptors form heteromers with A 2A or A 2B receptors and with other purinergic receptors, for example, P2Y1 and others, which alters responses mediated by constituent receptors, their sensitivity to endogenous adenosine, ligand binding, and may induce their cross‐antagonism . As some of adenosine heteromers, for example, A 1 with A 2A , and A 2B receptors are localized on glutamatergic terminals, their activation by enhanced endogenous adenosine may mask the antagonistic effect of DPCPX on adenosine A 1 receptor in some brain regions where zif‐268 was analyzed.…”

Adenosine A2B receptor activation stimulates glucose uptake in the mouse forebrain

“…This is because glutamatergic neurotransmission is a costly process, being responsible for the majority of energetic glucose metabolism in the brain [3]. In concert with this, we recently found that A 2B Rs modulate glutamatergic synaptic transmission in the hippocampus [19]. Not only neurons but also astrocytes are equipped with A 2B R [39,44], and both cell types are capable of releasing glutamate [45].…”

“…Notably, A 2B R have been implicated in peripheral glucose homeostasis [15,16] and have been proposed to control astrocytic glycogen metabolism [17,18]. Furthermore, we recently observed that A 2B Rs control A 1 receptor (A 1 R)-mediated responses in hippocampal glutamatergic synapses [19]. These observations prompt the attractive hypothesis that A 2B R may be associated with cerebral glucoregulation, especially when a metabolic boost is needed.…”

Regulation of neuronal communication by G protein‐coupled receptors

“…Interestingly, studies have also shown that the A 1 Rs and A 2A Rs form heterodimers that are involved in modulation neurotransmission with stimulation of the A 2A Rs leading to a decrease in agonist affinity for the A 1 Rs [113]. Although the A 2B Rs are expressed at low levels in comparison to the A 2A R in the hippocampus, this receptor has also been shown to regulate A 1 R-mediated inhibition of synaptic transmission [114].…”