Differential effects of rapamycin treatment on tonic and phasic GABAergic inhibition in dentate granule cells after focal brain injury in mice.
Differential effects of rapamycin treatment on tonic and phasic GABAergic inhibition in dentate granule cells after focal brain injury in mice.
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DOI：
10.1016/j.expneurol.2016.03.022
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发表时间：
2016-06
影响因子：
5.3
通讯作者：
Smith BN
中科院分区：
文献类型：
--
作者：
Butler CR;Boychuk JA;Smith BN
外伤性脑损伤（TBI）后导致创伤后癫痫（PTE）的一系列事件尚不清楚。海马形成和齿状回抑制改变是包括TBI和PTE在内的多种神经系统疾病的标志。海马抑制性突触信号主要由γ-氨基丁酸（GABA）神经传递驱动，并由突触后a型GABA受体（GABAAR’s）介导。这些参与神经元膜强直抑制的受体亚群在维持抑制状态中起着重要作用，在TBI和癫痫动物模型中，gabaar介导的强直抑制在功能上都发生了改变。在这项研究中，我们评估了mTOR抑制对控制性皮质冲击（CCI）后海马门部抑制性中间神经元损失和齿状回颗粒细胞（DGCs）突触和强直性gaba能抑制的影响，以确定TBI后mTOR激活是否调节GABAAR功能。与对侧半球和假对照组相比，CCI损伤后72小时，同侧半球背侧三分之二的Hilar抑制性中间神经元密度显著降低。雷帕霉素治疗并没有改变细胞密度的减少。损伤后1-2周和8-13周对DGCs进行的突触和强直电流测量显示，损伤后两个时间点，CCI损伤同侧DGCs的突触抑制和thip诱导的强直电流密度均有所降低，而静息时gabaar介导的强直电流没有变化。雷帕霉素治疗并没有改变cci损伤后1-2周同侧DGCs突触抑制降低的现象，但在损伤后8-13周，雷帕霉素治疗进一步降低了同侧DGCs的突触抑制。然而，在两个时间点，雷帕霉素治疗均可阻止损伤后thip诱导的紧张电流的减少。因此，雷帕霉素治疗可以不同地改变cci诱导的DGCs突触和强直性gabaar介导电流的变化。
The cascade of events leading to post-traumatic epilepsy (PTE) after traumatic brain injury (TBI) remains unclear. Altered inhibition in the hippocampal formation and dentate gyrus is a hallmark of several neurological disorders, including TBI and PTE. Inhibitory synaptic signaling in the hippocampus is predominately driven by γ-aminobutyric acid (GABA) neurotransmission, and is prominently mediated by postsynaptic type A GABA receptors (GABAAR's). Subsets of these receptors involved in tonic inhibition of neuronal membranes serve a fundamental role in maintenance of inhibitory state, and GABAAR-mediated tonic inhibition is altered functionally in animal models of both TBI and epilepsy. In this study we assessed the effect of mTOR inhibition on hippocampal hilar inhibitory interneuron loss and synaptic and tonic GABAergic inhibition of dentate gyrus granule cells (DGCs) after controlled cortical impact (CCI), to determine if mTOR activation after TBI modulates GABAAR function. Hilar inhibitory interneuron density was significantly reduced 72 hours after CCI injury in the dorsal two-thirds of the hemisphere ipsilateral to injury compared to the contralateral hemisphere and sham controls. Rapamycin treatment did not alter this reduction in cell density. Synaptic and tonic current measurements made in DGCs at both 1-2 and 8-13 weeks post-injury indicated reduced synaptic inhibition and THIP-induced tonic current density in DGCs ipsilateral to CCI injury at both time points post-injury, with no change in resting tonic GABAAR-mediated currents. Rapamycin treatment did not alter the reduced synaptic inhibition observed in ipsilateral DGCs 1-2 weeks post-CCI injury, but further reduced synaptic inhibition of ipsilateral DGCs at 8-13 weeks post-injury. The reduction in THIP-induced tonic current after injury, however, was prevented by rapamycin treatment at both time points. Rapamycin treatment thus differentially modifies CCI-induced changes in synaptic and tonic GABAAR-mediated currents in DGCs.