Necessary, but not sufficient: insights into the mechanisms of mGluR mediated long-term depression from a rat model of early life seizures.
Necessary, but not sufficient: insights into the mechanisms of mGluR mediated long-term depression from a rat model of early life seizures.
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DOI：
10.1016/j.neuropharm.2014.04.011
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发表时间：
2014-09
影响因子：
4.7
通讯作者：
Benke TA
中科院分区：
文献类型：
--
作者：
Bernard PB;Castano AM;Bayer KU;Benke TA
使用大鼠模型的早期生活癫痫发作（ELS），这夸大了mGluR介导的突触强度的长期抑制（mGluR-LTD）在成年期，我们探讨了潜在的mGluR-LTD诱导的信号级联。几种抑制剂完全阻断了对照组的mGluR-LTD，但在ELS大鼠中没有：蛋白酶体、雷帕霉素的哺乳动物靶蛋白（mTOR）、S6激酶（S6 K）或L型电压门控钙通道（L型VGCC）。抑制Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）导致对照大鼠中mGluR-LTD几乎完全阻断，ELS大鼠中mGluR-LTD略有减少。在ELS大鼠中发现“自主”CaMKII上调，而先前描述了由mTOR刺激的升高的S6 K活性。因此，这些因素中的每一个的调节对于对照大鼠中的mGluR-LTD诱导是必要的，但即使它们在ELS大鼠中的组合的永久激活也不足以单独支持ELS后的mGluR-LTD诱导。这意味着，虽然这些因素可能会依次在控制介导mGluR-LTD，这不再是ELS后的情况。相反，激活ERK被发现在ELS大鼠中显著下调。在对照大鼠中抑制MEK/ERK活化使mGluR-LTD升高至在ELS大鼠中观察到的夸大水平。总之，这些结果阐明了ELS后持续增强mGluR-LTD的机制和正常mGluR-LTD的潜在机制，为介导mGluR-LTD诱导的多个会聚途径提供了证据。在我们之前的工作中，这将这些信号级联与ELS行为表型联系起来，包括异常的工作记忆，恐惧条件反射和社会化。
Using the rat model of early life seizures (ELS), which has exaggerated mGluR mediated long-term depression of synaptic strength (mGluR-LTD) in adulthood, we probed the signaling cascades underlying mGluR-LTD induction. Several inhibitors completely blocked mGluR-LTD in control but not in ELS rats: the proteasome, the mammalian target of rapamycin (mTOR), S6 kinase (S6K), or L-type voltage-gated calcium channels (L-type VGCC). Inhibition of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) resulted in a near complete block of mGluR-LTD in control rats and a slight reduction of mGluR-LTD in ELS rats. “Autonomous” CaMKII was found to be upregulated in ELS rats, while elevated S6K activity, which is stimulated by mTOR, was described previously. Thus, modulation of each of these factors was necessary for mGluR-LTD induction in control rats, but even their combined, permanent activation in the ELS rats was not sufficient to individually support mGluR-LTD induction following ELS. This implies that while these factors may act sequentially in controls to mediate mGluR-LTD, this is no longer the case after ELS. In contrast, activated ERK was found to be significantly down-regulated in ELS rats. Inhibition of MEK/ERK activation in control rats elevated mGluR-LTD to the exaggerated levels seen in ELS rats. Together, these results elucidate both the mechanisms that persistently enhance mGluR-LTD after ELS and the mechanisms underlying normal mGluR-LTD by providing evidence for multiple, convergent pathways that mediate mGluR-LTD induction. With our prior work, this ties these signaling cascades to the ELS behavioral phenotype that includes abnormal working memory, fear conditioning and socialization.
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影响因子：
8.2
作者：
Coultrap, Steven J.;Vest, Rebekah S.;Ashpole, Nicole M.;Hudmon, Andy;Bayer, K. Ulrich
通讯作者：
Bayer, K. Ulrich
影响因子：
6.1
作者：
Chevere-Torres, Itzamarie;Kaphzan, Hanoch;Bhattacharya, Aditi;Kang, Areum;Maki, Jordan M.;Gambello, Michael J.;Arbiser, Jack L.;Santini, Emanuela;Klann, Eric
通讯作者：
Klann, Eric
影响因子：
11.2
作者：
Cornejo, Brandon J.;Mesches, Michael H.;Benke, Timothy A.
通讯作者：
Benke, Timothy A.
影响因子：
56.9
作者：
Huber, KM;Kayser, MS;Bear, MF
通讯作者：
Bear, MF
DOI：
10.1111/j.1460-9568.2009.06950.x
发表时间：
2009-10
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Citri A;Soler-Llavina G;Bhattacharyya S;Malenka RC
通讯作者：
Malenka RC