Enduring changes in tonic GABAA receptor signaling in dentate granule cells after controlled cortical impact brain injury in mice
Enduring changes in tonic GABAA receptor signaling in dentate granule cells after controlled cortical impact brain injury in mice
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DOI：
10.1016/j.expneurol.2016.01.005
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发表时间：
2016-03-01
影响因子：
5.3
通讯作者：
Smith, Bret N.
中科院分区：
文献类型：
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作者：
Boychuk, Jeffery A.;Butler, Corwin R.;Smith, Bret N.
海马中功能性GABA（A）R信号传导的变化先前已使用弥漫性脑损伤或极端局灶性脑损伤的临床前动物模型进行了评价，所述模型排除了位于损伤同侧的细胞的测量。因此，很少有关于位于局灶性脑损伤同侧的齿状颗粒细胞（DGC）中功能性GABA（A）R信号传导状态的信息，其中已记录了显著的细胞变化。采用全细胞膜片钳技术，观察了大鼠大脑皮质撞击伤后1 ~ 2、3 ~ 5、8-13周海马齿状回颗粒细胞GABA（A）受体的变化。在基线条件下和应用GABA（A）R激动剂4，5，6，7-四氢异恶唑并[5，4-c]吡啶-3-醇盐酸盐（THIP）期间，测量DGC中的突触和紧张性GABA（A）R电流（I-TronicGABA），以评估含有8个亚基的GABA（A）R的功能。CCI同侧的DGC在静息I-TonicGABA的幅度上相对于假损伤后或CCI对侧的DGC没有变化。相反，在两个时间点，CCI同侧的DGC中THIP诱发的I-TronicGABA显著减少。对损伤同侧的DGCs的紧张性GABA能抑制也表现出对神经类固醇THDOC的反应性降低。CCI同侧DGC中的I-TonicGABA对L 655，708（一种对含有α（5）亚基的GABA（A）Rs具有选择性的反向激动剂）的敏感性没有表现出变化，表明含有该亚基的GABA（A）Rs缺乏功能变化。在8-13周的时间点，GABA（A）R亚单位的基因表达预期有助于I-TronicGABA（即，在离体齿状回中，CCI损伤没有显著改变α（4）、α（5）和δ）。总的来说，这些结果表明，局灶性脑损伤同侧DGC中I-张力性GABA的持久功能变化与基因表达的改变无关。(C)2016爱思唯尔公司保留所有权利。
Changes in functional GABA(A)R signaling in hippocampus have previously been evaluated using pre-clinical animal models of either diffuse brain injury or extreme focal brain injury that precludes measurement of cells located ipsilateral to injury. As a result, there is little information about the status of functional GABA(A)R signaling in dentate granule cells (DGCs) located ipsilateral to focal brain injury, where significant cellular changes have been documented. We used whole-cell patch-clamp recordings from hippocampal slices to measure changes in GABA(A)Rs in dentate granule cells (DGCs) at 1-2,3-5, and 8-13 weeks after controlled cortical impact (CCI) brain injury. Synaptic and tonic GABA(A)R currents (I-TronicGABA) were measured in DGCs at baseline conditions and during application of the GABA(A)R agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol hydrochloride (THIP) to assess in the function of 8 subunit-containing GABA(A)Rs. DGCs ipsilateral to CCI exhibited no changes in the amplitude of resting I-TonicGABA relative to DGCs after sham-injury or contralateral to CCI. In contrast, there was a significant reduction in the THIP-evoked I-TronicGABA in DGCs ipsilateral to CCI at both time-points. Tonic GABAergic inhibition of DGCs ipsilateral to injury also exhibited reduced responsiveness to the neurosteroid THDOC. I-TonicGABA in DGCs ipsilateral to CCI did not exhibit a change in sensitivity to L655,708, an inverse agonist with selectivity for alpha(5) subunit-containing GABA(A)Rs, suggesting a lack of functional change in GABA(A)Rs containing this subunit. At the 8-13 week time-point, gene expression of GABA(A)R subunits expected to contribute to I-TronicGABA (i.e., alpha(4), alpha(5) and delta) was not significantly altered by CCI injury in isolated dentate gyrus. Collectively, these results demonstrate enduring functional changes in I-TonicGABA in DGCs ipsilateral to focal brain injury that occur independent of altered gene expression. (C) 2016 Elsevier Inc All rights reserved.