JAK/STAT pathway regulation of GABAA receptor expression after differing severities of experimental TBI.
JAK/STAT pathway regulation of GABAA receptor expression after differing severities of experimental TBI.
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DOI：
10.1016/j.expneurol.2015.07.001
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发表时间：
2015-09
影响因子：
5.3
通讯作者：
Brooks-Kayal AR
中科院分区：
文献类型：
--
作者：
Raible DJ;Frey LC;Del Angel YC;Carlsen J;Hund D;Russek SJ;Smith B;Brooks-Kayal AR
成年大脑中的突触抑制主要由γ - 氨基丁酸（GABA）A 型受体（GABAAR）介导。这些受体的分布、特性和动力学在很大程度上由其亚基组成决定。创伤性脑损伤（TBI）后亚基组成的改变可能导致突触放电异常增加，并可能促成与损伤相关的病理变化。几项研究表明，Janus激酶/信号转导和转录激活因子（JAK/STAT）信号通路能够改变GABAAR亚基的表达。本研究利用控制性皮质撞击（CCI）模型，研究了小鼠在两种不同严重程度的实验性TBI后JAK/STAT通路激活的变化。还研究了在严重控制性皮质撞击（CCI - S）后用JAK/STAT抑制剂（WP1066）调节JAK/STAT通路的激活是否会改变创伤后癫痫的发展和/或损伤后的神经功能恢复。我们的结果表明，STAT3的激活以及GABAAR α1和γ2亚基水平的表达都有不同的变化，这些变化取决于损伤的严重程度。GABAAR α1亚基水平的变化似乎至少部分是由转录介导的。在CCI损伤后，我们能够通过WP1066治疗选择性地逆转GABAAR α1蛋白水平的下降。WP1066治疗还改善了损伤后前庭运动功能的恢复程度。这些发现表明，在这个TBI小鼠模型中，JAK/STAT通路激活的程度和GABAAR α1亚基水平的下降取决于损伤的严重程度。此外，在严重的实验性TBI后降低JAK/STAT通路的激活可逆转GABAAR α1蛋白水平的下降，并改善前庭运动功能的恢复。
Synaptic inhibition in the adult brain is primarily mediated by the γ-aminobutyric acid (GABA) type A receptor (GABAAR). The distribution, properties, and dynamics of these receptors are largely determined by their subunit composition. Alteration of subunit composition after a traumatic brain injury (TBI) may result in abnormal increased synaptic firing and possibly contribute to injury-related pathology. Several studies have shown that the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway can alter GABAAR subunit expression. The present study investigated changes in JAK/STAT pathway activation after two different severities of experimental TBI in the mouse using the controlled cortical impact (CCI) model. It also investigated whether modulating the activation of the JAK/STAT pathway after severe controlled cortical impact (CCI-S) with a JAK/STAT inhibitor (WP1066) alters post-traumatic epilepsy development and/or neurological recovery after injury. Our results demonstrated differential changes in both the activation of STAT3 and the expression of the GABAAR α1 and γ2 subunit levels that were dependent on the severity of the injury. The change in the GABAAR α1 subunit levels appeared to be at least partly transcriptionally mediated. We were able to selectively reverse the decrease in GABAAR α1 protein levels with WP1066 treatment after CCI injury. WP1066 treatment also improved the degree of recovery of vestibular motor function after injury. These findings suggest that the magnitude of JAK/STAT pathway activation and GABAAR α1 subunit level decrease is dependent on injury severity in this mouse model of TBI. In addition, reducing JAK/STAT pathway activation after severe experimental TBI reverses the decrease in the GABAAR α1 protein levels and improves vestibular motor recovery.
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影响因子：
11.2
作者：
Hussain, S. Farzana;Kong, Ling-Yuan;Heimberger, Amy B.
通讯作者：
Heimberger, Amy B.
影响因子：
2.2
作者：
Kharatishvili, Irina;Pitkanen, Asla
通讯作者：
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影响因子：
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影响因子：
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作者：
Grabenstatter HL;Del Angel YC;Carlsen J;Wempe MF;White AM;Cogswell M;Russek SJ;Brooks-Kayal AR
通讯作者：
Brooks-Kayal AR
影响因子：
4.7
作者：
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通讯作者：
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