Astrocytes potentiate GABAergic transmission in the thalamic reticular nucleus via endozepine signaling
Astrocytes potentiate GABAergic transmission in the thalamic reticular nucleus via endozepine signaling
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DOI：
10.1073/pnas.1318031110
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发表时间：
2013-12-10
影响因子：
11.1
通讯作者：
Huguenard, John R.
中科院分区：
文献类型：
--
作者：
Christian, Catherine A.;Huguenard, John R.
新出现的证据表明，地西泮结合抑制剂（DBI）介导的内源性苯二氮卓类（endozepine）对丘脑网状核（nRT）的突触抑制作用。在这里，我们表明，DBI肽共定位与星形胶质细胞和神经元标记物在小鼠nRT，并调查星形胶质细胞功能的作用，在这个核内的内分泌调节通过测试的影响，神经胶质毒素氟柠檬酸（FC）的突触抑制和内分泌信号在nRT使用膜片钳记录。FC处理降低了WT小鼠中GABA（A）受体（GABA（A）R）介导的自发抑制性突触后电流的有效抑制电荷，表明星形胶质细胞增强了nRT中的GABA（A）R反应。这种效应被抑制经典苯二氮卓类与含有α 3亚基（主要在nRT中）的GABA（A）Rs结合的点突变和去除Dbi基因的染色体缺失所消除。因此，星形胶质细胞是通过DBI肽家族内皮素通过α 3亚基苯二氮卓结合位点进行正向变构调节所必需的。从邻近的腹基底核（ventrobasal nucleus）中的神经元（不含endozepines）中取出的外向嗅探器贴片显示，当放置在nRT中时，对笼状GABA的激光光刺激的反应增强。FC治疗阻断了这种反应的nRT依赖性增强，苯二氮卓类位点拮抗剂氟马西尼也是如此。然而，当嗅探器补丁被放置在ventrobasal核，随后的治疗与FC导致增强的uncaged GABA反应，这表明丘脑星形胶质细胞在调节抑制的核特异性作用。两者合计，这些结果表明，星形胶质细胞所需的nRT中的endozepine行动，因此可以是突触抑制的积极调节剂。
Emerging evidence indicates that diazepam-binding inhibitor (DBI) mediates an endogenous benzodiazepine-mimicking (endozepine) effect on synaptic inhibition in the thalamic reticular nucleus (nRT). Here we demonstrate that DBI peptide colocalizes with both astrocytic and neuronal markers in mouse nRT, and investigate the role of astrocytic function in endozepine modulation in this nucleus by testing the effects of the gliotoxin fluorocitrate (FC) on synaptic inhibition and endozepine signaling in the nRT using patch-clamp recordings. FC treatment reduced the effective inhibitory charge of GABA(A) receptor (GABA(A)R)-mediated spontaneous inhibitory postsynaptic currents in WT mice, indicating that astrocytes enhance GABA(A)R responses in the nRT. This effect was abolished by both a point mutation that inhibits classical benzodiazepine binding to GABA(A)Rs containing the alpha 3 subunit (predominant in the nRT) and a chromosomal deletion that removes the Dbi gene. Thus, astrocytes are required for positive allosteric modulation via the alpha 3 subunit benzodiazepine-binding site by DBI peptide family endozepines. Outside-out sniffer patches pulled from neurons in the adjacent ventrobasal nucleus, which does not contain endozepines, show a potentiated response to laser photostimulation of caged GABA when placed in the nRT. FC treatment blocked the nRT-dependent potentiation of this response, as did the benzodiazepine site antagonist flumazenil. When sniffer patches were placed in the ventrobasal nucleus, however, subsequent treatment with FC led to potentiation of the uncaged GABA response, suggesting nucleus-specific roles for thalamic astrocytes in regulating inhibition. Taken together, these results suggest that astrocytes are required for endozepine actions in the nRT, and as such can be positive modulators of synaptic inhibition.