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

在最初的18分钟内，腺苷（100nM）增加了从颗粒细胞层引起的群体峰值（ps）的幅度，在整个应用过程中都很明显，并且在药物洗出30分钟时效果逆转。选择性A_<2a>腺苷受体拮抗剂DMPX和选择性A_<2a>腺苷受体激动剂CGS21680 （0.1 μM）可抑制PS振幅的增加，其增强程度与腺苷相似，提示腺苷对海马神经传递的促进作用是由A_<2a>腺苷受体介导的。谷氨酸转运蛋白抑制剂PDC也有类似的促进作用；PDC逐渐增加PS振幅，在120分钟时达到180%左右，在药物洗出30分钟后效果逆转。值得注意的是，PDC对神经传递的饱和作用阻断了腺苷对神经传递的增强作用，表明腺嘌呤的促进作用与PDC具有共同的机制。换句话说，腺苷通过靶向谷氨酸转运体促进神经传递。为了研究腺苷是否真的作用于胶质谷氨酸转运体，我们在非洲爪蟾卵母细胞中表达了A_1或A_<2a>腺苷受体与GLT-1。当A_<2a>腺苷受体与GLT-1共表达时，A_<2a>腺苷受体的激活对谷氨酸诱发电流的抑制作用为对照的56%，DMPX可抑制该作用。相比之下，在共表达GLT-1和A_1腺苷受体的卵母细胞中，A_1腺苷受体的激活不影响GLT-1电流，这表明腺苷通过腺苷A_<2a>受体抑制GLT-1谷氨酸摄取。综上所述，腺苷通过A_<2a>腺苷受体阻断胶质细胞GLT-1，从而增加突触谷氨酸浓度，从而促进海马神经传递。这可能是腺苷促进海马神经传递的细胞机制。少

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