Metabotropic glutamate receptor-dependent long-term depression is impaired due to elevated ERK signaling in the ΔRG mouse model of tuberous sclerosis complex.
Metabotropic glutamate receptor-dependent long-term depression is impaired due to elevated ERK signaling in the ΔRG mouse model of tuberous sclerosis complex.
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DOI：
10.1016/j.nbd.2011.12.028
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发表时间：
2012-03
影响因子：
6.1
通讯作者：
Klann, Eric
中科院分区：
文献类型：
--
作者：
Chevere-Torres, Itzamarie;Kaphzan, Hanoch;Bhattacharya, Aditi;Kang, Areum;Maki, Jordan M.;Gambello, Michael J.;Arbiser, Jack L.;Santini, Emanuela;Klann, Eric
结节性硬化症 (TSC) 和脆性 X 综合征 (FXS) 是由翻译负调节因子突变引起的。 FXS 模型小鼠表现出增强的代谢型谷氨酸受体依赖性长期抑郁 (mGluR-LTD)。因此，我们假设 TSC 小鼠模型（ΔRG 转基因小鼠）也会表现出增强的 mGluR-LTD。我们测量了 ΔRG 转基因小鼠中 TSC2-GAP 突变对 mTORC1 和 ERK 信号通路以及蛋白质合成依赖性海马突触可塑性的影响。这些小鼠表达与 TSC1 结合的显性/阴性 TSC2，但其 GAP 结构域存在缺失和取代突变，导致复合物失活。与之前对其他几个 TSC 模型小鼠系的研究一致，我们观察到 ΔRG 小鼠大脑中 S6 磷酸化升高，表明翻译上调。令人惊讶的是，mGluR-LTD 在 ΔRG 转基因小鼠中并未增强，而是受损，表明 TSC 和 FXS 具有不同的突触可塑性表型。与 TSC 患者类似，ΔRG 转基因小鼠表现出 ERK 信号增强。此外，MEK-ERK 抑制剂 U0126 可以挽救 ΔRG 转基因小鼠表现出的 mGluR-LTD 损伤。我们的结果表明，在 ΔRG 小鼠中观察到的 mGluR-LTD 损伤涉及异常的 TSC1/2-ERK 信号传导。
Tuberous sclerosis complex (TSC) and fragile X syndrome (FXS) are caused by mutations in negative regulators of translation. FXS model mice exhibit enhanced metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD). Therefore, we hypothesized that a mouse model of TSC, ΔRG transgenic mice, also would exhibit enhanced mGluR-LTD. We measured the impact of TSC2-GAP mutations on the mTORC1 and ERK signaling pathways and protein synthesis-dependent hippocampal synaptic plasticity in ΔRG transgenic mice. These mice express a dominant/negative TSC2 that binds to TSC1, but has a deletion and substitution mutation in its GAP-domain, resulting in inactivation of the complex. Consistent with previous studies of several other lines of TSC model mice, we observed elevated S6 phosphorylation in the brains of ΔRG mice, suggesting upregulated translation. Surprisingly, mGluR-LTD was not enhanced, but rather was impaired in the ΔRG transgenic mice, indicating that TSC and FXS have divergent synaptic plasticity phenotypes. Similar to patients with TSC, the ΔRG transgenic mice exhibit elevated ERK signaling. Moreover, the mGluR-LTD impairment displayed by the ΔRG transgenic mice was rescued with the MEK-ERK inhibitor U0126. Our results suggest that the mGluR-LTD impairment observed in ΔRG mice involves aberrant TSC1/2-ERK signaling.
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影响因子：
4.8
作者：
Karbowniczek, Magdalena;Robertson, Gavin P.;Henske, Elizabeth Petri
通讯作者：
Henske, Elizabeth Petri
影响因子：
4.8
作者：
Favata, MF;Horiuchi, KY;Trzaskos, JM
通讯作者：
Trzaskos, JM
DOI：
10.1523/jneurosci.1617-11.2011
发表时间：
2011-06-15
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bateup HS;Takasaki KT;Saulnier JL;Denefrio CL;Sabatini BL
通讯作者：
Sabatini BL
影响因子：
11.2
作者：
Jansen, An C.;Sancak, Ozgur;Andermann, Eva
通讯作者：
Andermann, Eva
影响因子：
11.2
作者：
Bhatia, Bobby;Northcott, Paul A.;Kenney, Anna Marie
通讯作者：
Kenney, Anna Marie