Astrocyte glutamate transporters regulate metabotropic glutamate receptor-mediated excitation of hippocampal Interneurons
Astrocyte glutamate transporters regulate metabotropic glutamate receptor-mediated excitation of hippocampal Interneurons
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DOI：
10.1523/jneurosci.5217-03.2004
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发表时间：
2004-05-12
影响因子：
5.3
通讯作者：
Bergles, DE
中科院分区：
文献类型：
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作者：
Huang, YHH;Sinha, SR;Bergles, DE
清除细胞外谷氨酸对于限制兴奋性突触的代谢性谷氨酸受体（mGluRs）的活性是必要的；然而，在神经元和胶质膜中发现的转运蛋白对这种摄取的相对贡献尚不清楚。位于脑脊液-肺泡边界的海马中间神经元表达mglur1 α，一种调节兴奋性和突触可塑性的代变谷氨酸受体。为了确定哪些谷氨酸转运体在这些兴奋性突触中对谷氨酸的去除是必需的，我们记录了急性海马切片中来自洞状取向分子（O-LM）中间神经元的mglur1介导的EPSCs。如果在刺激前短暂地去极化以允许Ca2+进入O-LM中间神经元，那么对取向层的刺激可靠地引发了mglur1介导的缓慢电流。谷氨酸转运体GLT-1的选择性抑制作用EAAT2（兴奋性氨基酸转运蛋白）]与二氢海碱盐将这些反应的幅度增加了大约三倍，表明这些转运蛋白与mGluRs竞争突触释放的谷氨酸。然而，TBOA （DL-threo-b-benzyloxyaspartic acid）对所有谷氨酸转运体的抑制使mGluR1 EPSCs >增加了15倍，这表明其他转运体也影响了这些受体的激活。为了鉴定这些转运体，我们在缺乏GLAST（谷氨酸-天冬氨酸转运体EAAT1）或EAAC1（兴奋性氨基酸载体EAAT3）的小鼠中检测了mGluR1 EPSCs。野生型小鼠和转运体敲除小鼠的反应对比显示，星形胶质细胞谷氨酸转运体GLT-1和GLAST，而不是神经元转运体EAAC1，限制了O-LM中间神经元中mGluRs的激活。mGluR1 EPSCs的转运蛋白依赖性增强导致中间神经元放电的急剧增加和CA1锥体神经元的抑制增强，这表明转运蛋白活性的急性或长期破坏可能导致网络活动的变化，这是由于中间神经元兴奋性增强的结果。
Clearance of extracellular glutamate is essential for limiting the activity of metabotropic glutamate receptors (mGluRs) at excitatory synapses; however, the relative contribution of transporters found in neuronal and glial membranes to this uptake is poorly understood. Hippocampal interneurons located at the oriens-alveus border express mGluR1alpha, a metabotropic glutamate receptor that regulates excitability and synaptic plasticity. To determine which glutamate transporters are essential for removing glutamate at these excitatory synapses, we recorded mGluR1-mediated EPSCs from oriens-lacunosum moleculare (O-LM) interneurons in acute hippocampal slices. Stimulation in stratum oriens reliably elicited a slow mGluR1-mediated current in O-LM interneurons if they were briefly depolarized to allow Ca2+ entry before stimulation. Selective inhibition of GLT-1 [for glutamate transporter; EAAT2 (for excitatory amino acid transporter)] with dihydrokainate increased the amplitude of these responses approximately threefold, indicating that these transporters compete with mGluRs for synaptically released glutamate. However, inhibition of all glutamate transporters with TBOA (DL-threo-b-benzyloxyaspartic acid) increased mGluR1 EPSCs > 15-fold, indicating that additional transporters also shape activation of these receptors. To identify these transporters, we examined mGluR1 EPSCs in mice lacking GLAST (for glutamate-aspartate transporter; EAAT1) or EAAC1 (for excitatory amino acid carrier; EAAT3). A comparison of responses recorded from wild-type and transporter knock-out mice revealed that the astroglial glutamate transporters GLT-1 and GLAST, but not the neuronal transporter EAAC1, restrict activation of mGluRs in O-LM interneurons. Transporter-dependent potentiation of mGluR1 EPSCs led to a dramatic increase in interneuron firing and enhanced inhibition of CA1 pyramidal neurons, suggesting that acute or prolonged disruption of transporter activity could lead to changes in network activity as a result of enhanced interneuron excitability.