ADENOSINE FACILITATES HIPPOCAMPAL NEUROTRANSMISSION BY BLOCKING GLIAL GLUTAMATE REUPTAKE VIA THE GLUTAMATE TRANSPORTER GLT-1

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Adenosine (100nM) increased the amplitude of population spikes (PSs) elicited from the granular cell layer, to approximately 150% of basal levels during the initial 18 min, being evident throughout application, and the effect reversed at 30-min washing-out of the drug. The increase was inhibited by the selective A_<2a> adenosine receptor antagonist, DMPX, and the selective A_<2a> adenosine receptor agonist, CGS21680 (0.1 μM) enhanced PS amplitude to a similar extent as adenosine did, suggesting that the facilitatory action of adenosine on hippocampal neurotransmission is mediated by A_<2a> adenosine receptors. A similar facilitation was found with the glutamate transporter inhibitor, PDC ; PDC gradually increased the PS amplitude, reaching about 180% at 120-min treatment, and the effect reversed 30 min after washing-out of the drug. Notably, the saturable effect of PDC on neurotransmission occluded the enhancement induced by adenosine, suggesting that the facilitatory actions of adenos … More ine and PDC share a common mechanism ; in other words, adenosine facilitates neurotransmission by targeting glutamate transporters. To examine whether adenosine actually acts on glial glutamate transporters or not, we expressed A_1 or A_<2a> adenosine receptors together with GLT-1 in Xenopus oocytes. When A_<2a> adenosine receptors were co-expressed with GLT-1, activation of A_<2a> adenosine receptors inhibited glutamate-evoked currents to 56% of control, and the effect was inhibited by DMPX.In contrast, GLT-1 currents were not affected by activation of A_1 adenosine receptors in oocytes co-expressing GLT-1 and A_1 adenosine receptors, indicating that adenosine inhibits GLT-1 glutamate uptake via adenosine A_<2a> receptors. Taken together, it appears that adenosine facilitates hippocampal neurotransmission as a result of increasing synaptic glutamate concentrations by blocking glial GLT-1 via A_<2a> adenosine receptors. This may represent the cellular mechanism underlying the facilitatory action of adenosine on hippocampal neurotransmission. Less