Adenosine A2B receptor down‐regulates metabotropic glutamate receptor 5 in astrocytes during postnatal development
Adenosine A2B receptor down‐regulates metabotropic glutamate receptor 5 in astrocytes during postnatal development
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腺苷 A2B 受体在出生后发育过程中下调星形胶质细胞中代谢型谷氨酸受体 5
DOI：
10.1002/glia.24006
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发表时间：
2021
期刊：
影响因子：
6.2
通讯作者：
Koizumi Schuichi
中科院分区：
文献类型：
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作者：
Tanaka Masayoshi;Shigetomi Eiji;Parajuli Bijay;Nagatomo Hiroaki;Shinozaki Youichi;Hirayama Yuri;Saito Kozo;Kubota Yuto;Danjo Yosuke;Lee Ji Hwan;Kim Sun Kwang;Nabekura Junichi;Koizumi Schuichi
星形胶质细胞中的代谢型谷氨酸受体5（mGluR 5）是控制突触重塑的关键分子。虽然mGluR 5在新生星形胶质细胞中含量丰富，但其水平在发育过程中逐渐下调，并且在成人中几乎不存在。然而，在一些病理条件下，mGluR 5重新出现在成年星形胶质细胞中，并通过形成不受控制的突触而导致疾病发病。因此，控制mGluR 5在星形胶质细胞中的表达对于几种疾病是至关重要的，但是调节mGluR 5表达的机制仍然未知。在这里，我们发现三磷酸腺苷（ATP）/腺苷介导的信号下调星形胶质细胞中的mGluR 5。首先，纳塔尔后7-P28天小鼠急性脑切片中星形胶质细胞的原位Ca 2+成像显示，由mGluR 5激动剂（S）-3，5-二羟基苯甘氨酸（DHPG）诱发的Ca 2+反应在发育过程中减少，而由ATP或其代谢物腺苷诱发的Ca 2+反应增加。其次，ATP和腺苷抑制培养的星形胶质细胞中mGluR 5基因Grm 5的表达。第三，DHPG诱发的Ca 2+反应的减少与Grm 5的下调有关。有趣的是，在几种腺苷（P1）受体和ATP（P2）受体基因中，只有腺苷A2 B受体基因Adora 2b在发育过程中上调。事实上，我们观察到Adora 2b敲除星形胶质细胞在P14时Grm 5的下调受到抑制，Adora 2b敲除小鼠的原位Ca 2+成像表明A2 B受体抑制星形胶质细胞中mGluR 5的表达。此外，A2 B受体的缺失使发育期兴奋性突触数目增加。综上所述，A2 B受体对于星形胶质细胞中mGluR 5的下调至关重要，这将有助于终止发育期间的过度突触发生。
Metabotropic glutamate receptor 5 (mGluR5) in astrocytes is a key molecule for controlling synapse remodeling. Although mGluR5 is abundant in neonatal astrocytes, its level is gradually down‐regulated during development and is almost absent in the adult. However, in several pathological conditions, mGluR5 re‐emerges in adult astrocytes and contributes to disease pathogenesis by forming uncontrolled synapses. Thus, controlling mGluR5 expression in astrocyte is critical for several diseases, but the mechanism that regulates mGluR5 expression remains unknown. Here, we show that adenosine triphosphate (ATP)/adenosine‐mediated signals down‐regulate mGluR5 in astrocytes. First, in situ Ca2+imaging of astrocytes in acute cerebral slices from post‐natal day (P)7‐P28 mice showed that Ca2+responses evoked by (S)‐3,5‐dihydroxyphenylglycine (DHPG), a mGluR5 agonist, decreased during development, whereas those evoked by ATP or its metabolite, adenosine, increased. Second, ATP and adenosine suppressed expression of the mGluR5 gene,Grm5, in cultured astrocytes. Third, the decrease in the DHPG‐evoked Ca2+responses was associated with down‐regulation ofGrm5. Interestingly, among several adenosine (P1) receptor and ATP (P2) receptor genes, only the adenosine A2Breceptor gene,Adora2b, was up‐regulated in the course of development. Indeed, we observed that down‐regulation ofGrm5was suppressed inAdora2bknockout astrocytes at P14 and in situ Ca2+imaging fromAdora2bknockout mice indicated that the A2Breceptor inhibits mGluR5 expression in astrocytes. Furthermore, deletion of A2Breceptor increased the number of excitatory synapse in developmental stage. Taken together, the A2Breceptor is critical for down‐regulation of mGluR5 in astrocytes, which would contribute to terminate excess synaptogenesis during development.