Glutamate induces the elongation of early dendritic protrusions via mGluRs in wild type mice, but not in fragile X mice.
Glutamate induces the elongation of early dendritic protrusions via mGluRs in wild type mice, but not in fragile X mice.
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DOI：
10.1371/journal.pone.0032446
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Portera-Cailliau C
中科院分区：
文献类型：
--
作者：
Cruz-Martín A;Crespo M;Portera-Cailliau C
脆性X综合征(FXS)是自闭症和精神障碍中最常见的遗传病，其原因是Fmr1基因转录沉默，导致RNA结合蛋白FMRP丢失。在受影响的个体中，皮质锥体神经元的树突棘异常不成熟，在Fmr1基因敲除(KO)小鼠中，它们也异常不稳定。这可能会导致突触发生的缺陷，因为脊柱动力学对突触的形成至关重要。我们之前已经证明，最早的树突突起是高度动态的，可能起到伸展轴突的探索作用，对谷氨酸的反应是延长的。在这里，我们测试了这一过程是由代谢性谷氨酸受体(MGluRs)介导的假设，并且它在Fmr1 KO小鼠中是有缺陷的。用双光子显微镜对出生后早期小鼠的急性脑片进行时间推移成像，我们发现谷氨酸或1组mGluR激动剂DHPG使第2/3层神经元的早期树突突起变长。阻断mGluR5信号，逆转KO小鼠的一些成体表型，阻止谷氨酸介导的早期突起的延长。相比之下，KO小鼠的树突状突起对谷氨酸没有反应。因此，FMRP的缺失可能会损害皮质锥体神经元对附近突触前终末释放的谷氨酸的反应能力，这可能是启动突触发生和稳定脊髓的关键步骤。
Fragile X syndrome (FXS), the most common inherited from of autism and mental impairment, is caused by transcriptional silencing of the Fmr1 gene, resulting in the loss of the RNA-binding protein FMRP. Dendritic spines of cortical pyramidal neurons in affected individuals are abnormally immature and in Fmr1 knockout (KO) mice they are also abnormally unstable. This could result in defects in synaptogenesis, because spine dynamics are critical for synapse formation. We have previously shown that the earliest dendritic protrusions, which are highly dynamic and might serve an exploratory role to reach out for axons, elongate in response to glutamate. Here, we tested the hypothesis that this process is mediated by metabotropic glutamate receptors (mGluRs) and that it is defective in Fmr1 KO mice. Using time-lapse imaging with two-photon microscopy in acute brain slices from early postnatal mice, we find that early dendritic protrusions in layer 2/3 neurons become longer in response to application of glutamate or DHPG, a Group 1 mGluR agonist. Blockade of mGluR5 signaling, which reverses some adult phenotypes of KO mice, prevented the glutamate-mediated elongation of early protrusions. In contrast, dendritic protrusions from KO mice failed to respond to glutamate. Thus, absence of FMRP may impair the ability of cortical pyramidal neurons to respond to glutamate released from nearby pre-synaptic terminals, which may be a critical step to initiate synaptogenesis and stabilize spines.
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影响因子：
14.8
作者：
Holtmaat, Anthony;Bonhoeffer, Tobias;Chow, David K.;Chuckowree, Jyoti;De Paola, Vincenzo;Hofer, Sonja B.;Huebener, Mark;Keck, Tara;Knott, Graham;Lee, Wei-Chung A.;Mostany, Ricardo;Mrsic-Flogel, Tom D.;Nedivi, Elly;Portera-Cailliau, Carlos;Svoboda, Karel;Trachtenberg, Joshua T.;Wilbrecht, Linda
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通讯作者：
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影响因子：
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