期刊
GLIA
卷 69, 期 11, 页码 2546-2558出版社
WILEY
DOI: 10.1002/glia.24006
关键词
adenosine; adenosine A(2B) receptor; astrocytes; ATP; development; mGluR5
资金
- Core Research for Evolutional Science and Technology
- Frontier in Brain Science Program in University of Yamanashi
- Japan Agency for Medical Research and Development
- Takeda Medical Research Foundation
- National Research Foundation of Korea [NRF-2019R1A2C2086052]
- Mitsubishi Foundation
- Takeda Science Foundation
- Japan Society for the Promotion of Science [KAKENHI 18H0512, KAKENHI 19H04746, KAKENHI 20H05060, KAKENHI 20H05902, KAKENHI JP25117003]
mGluR5 in astrocytes is regulated by ATP/adenosine signals, which helps control synapse remodeling and potentially contributes to disease pathogenesis.
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 of Grm5. Interestingly, among several adenosine (P1) receptor and ATP (P2) receptor genes, only the adenosine A(2B) receptor gene, Adora2b, was up-regulated in the course of development. Indeed, we observed that down-regulation of Grm5 was suppressed in Adora2b knockout astrocytes at P14 and in situ Ca2+ imaging from Adora2b knockout mice indicated that the A(2B) receptor inhibits mGluR5 expression in astrocytes. Furthermore, deletion of A(2B) receptor increased the number of excitatory synapse in developmental stage. Taken together, the A(2B) receptor is critical for down-regulation of mGluR5 in astrocytes, which would contribute to terminate excess synaptogenesis during development.
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