Astrocytic activation of A1 receptors regulates the surface expression of NMDA receptors through a Src kinase dependent pathway.
Astrocytic activation of A1 receptors regulates the surface expression of NMDA receptors through a Src kinase dependent pathway.
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DOI：
10.1002/glia.21181
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发表时间：
2011-07
期刊：
影响因子：
6.2
通讯作者：
Haydon, Philip G.
中科院分区：
文献类型：
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作者：
Deng, Qiudong;Terunuma, Miho;Fellin, Tommaso;Moss, Stephen J.;Haydon, Philip G.
从星形胶质细胞释放的化学递质，称为胶质递质，调节突触传递和神经元功能。利用星形胶质细胞特异的可诱导转基因小鼠(dnSNARE小鼠)，我们已经证明，抑制胶质传递会导致腺苷A1受体(A1R)的激活减少，并破坏睡眠稳态(；)。此外，在这些星形胶质细胞特异性转基因动物中，突触N-甲基-D-天冬氨酸受体(NMDAR)电流减少。由于腺苷和NMDA受体在睡眠过程中的重要性，我们询问A1R激活的变化和突触NMDA受体之间是否存在因果联系。我们发现星形细胞dnSNARE的表达导致Src激酶和NR2亚基的酪氨酸磷酸化水平降低，同时伴随着NR2亚基表面表达的降低。为了测试A1R信号在介导这些作用中的作用，我们发现野生型(WT)切片与A1R拮抗剂孵育后，减少了Src激酶和NR2B的酪氨酸磷酸化，减少了NR2B亚单位的表面表达，并导致小型EpSCs的NMDA成分较小。在dnSNARE小鼠中，我们可以通过在A1R激动剂中孵育来挽救WT表型：A1受体的激活导致Src激酶和NR2B亚单位的酪氨酸磷酸化增加，NR2B亚单位的表面表达增加，突触mEPSC的NMDA成分增加。这些结果首次证明，星形胶质细胞可以通过激活特定的细胞内信号通路来调节NMDA受体的表面表达，从而在长时间尺度上影响神经元的兴奋性。
Chemical transmitters released from astrocytes, termed gliotransmitters, modulate synaptic transmission and neuronal function. Using astrocyte-specific inducible transgenic mice (dnSNARE mice), we have demonstrated that inhibiting gliotransmission leads to reduced activation of adenosine A1 receptors (A1R) and impaired sleep homeostasis (;). Additionally, synaptic N-methyl-D-aspartate receptor (NMDAR) currents are reduced in these astrocyte-specific transgenic animals. Because of the importance of adenosine and NMDA receptors to sleep processes we asked whether there is a causal linkage between changes in A1R activation and synaptic NMDA receptors. We show that astrocytic dnSNARE expression leads to reduced tyrosine phosphorylation of Src kinase and NR2 subunits concomitant with the decreased surface expression of the NR2 subunits. To test the role of A1R signaling in mediating these actions, we show that incubation of wildtype (WT) slices with an A1R antagonist reduces tyrosine phosphorylation of Src kinase and NR2B, decreases the surface expression of the NR2B subunits and leads to smaller NMDA component of miniature EPSCs. In dnSNARE mice we could rescue WT phenotype by incubation in an A1R agonist: activation of A1 receptor led to increased tyrosine phosphorylation of Src kinase and NR2B subunits as well as increased the surface expression of the NR2B subunit and increased NMDA component of the synaptic mEPSC. These results provide the first demonstration that astrocytes can affect neuronal excitability on a long time scale by regulating the surface expression of NMDA receptors through the activation of specific intracellular signaling pathways.
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影响因子：
56.9
作者：
Pascual, O;Casper, KB;Haydon, PG
通讯作者：
Haydon, PG
影响因子：
16.2
作者：
Ehlers, MD
通讯作者：
Ehlers, MD
影响因子：
4.8
作者：
LAU, LF;HUGANIR, RL
通讯作者：
HUGANIR, RL
DOI：
10.1073/pnas.92.9.3948
发表时间：
1995-04-25
影响因子：
11.1
作者：
SCHELL, MJ;MOLLIVER, ME;SNYDER, SH
通讯作者：
SNYDER, SH
影响因子：
64.8
作者：
通讯作者：
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