Insulin promotes dendritic spine and synapse formation by the PI3K/Akt/mTOR and Rac1 signaling pathways
Insulin promotes dendritic spine and synapse formation by the PI3K/Akt/mTOR and Rac1 signaling pathways
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DOI：
10.1016/j.neuropharm.2011.06.003
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发表时间：
2011-09-01
影响因子：
4.7
通讯作者：
Hsu, Kuei-Sen
中科院分区：
文献类型：
--
作者：
Lee, Cheng-Che;Huang, Chiung-Chun;Hsu, Kuei-Sen
胰岛素及其受体在大脑中广泛表达，并被认为在突触可塑性中起着关键作用。尽管树突棘的结构重塑与突触可塑性的稳定表达有关，但胰岛素受体(IR)信号在树突棘的建立和动态变化中的作用尚不清楚。在此，我们报道了胰岛素促进大鼠海马神经元原代培养树突棘的形成。相反，使用阻断抗体或短发夹状RNA(ShRNAs)下调IR信号导致树突棘数量减少，并导致微小兴奋性突触后电流(MEPSCs)频率显著降低，但不影响其幅度分布。药物阻断磷脂酰肌醇3-激酶(PI3K)/Akt/哺乳动物靶标雷帕霉素(MTOR)信号通路和小GTPase rac1特异性地阻止胰岛素诱导的树突棘密度的增加。同时，通过慢病毒感染shRNA基因消融了rac1的表达，消除了胰岛素诱导的树突棘的增加。更重要的是，随着胰岛素刺激树突棘密度的增加，突触前标记物染色密度增加，mEPSC频率增加。综上所述，这些结果揭示了IR信号通过激活PI3K/Akt/mTOR和rac1信号通路在调节海马神经元树突棘形成和兴奋性突触发育中的新作用。(C)2011爱思唯尔有限公司。保留所有权利。
Insulin and its receptor are broadly expressed throughout the brain and have been postulated to play a crucial role in synaptic plasticity. Although structural remodeling of dendritic spines is associated with stable expression of synaptic plasticity, the role of insulin receptor (IR) signaling in the establishment and dynamic changes of dendritic spines remains unclear. Here we report that insulin promotes dendritic spine formation in primary cultures of rat hippocampal neurons. Conversely, downregulation of IR signaling using a blocking antibody or short hairpin RNAs (shRNAs) resulted in a decrease in number of dendritic spines and caused a significant reduction in the frequency of miniature excitatory postsynaptic currents (mEPSCs) without affecting the distribution of their amplitudes. Pharmacological blockade of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway and the small GTPase Rac1 specifically prevented the insulin-induced increase in dendritic spine density. In parallel, genetic ablation of Rac1 expression by lentiviral infection with shRNA abrogated the increase in dendritic spines induced by insulin. More importantly, the increase in dendritic spine density by insulin was accompanied by increasing in presynaptic marker staining density and displayed an increase in mEPSC frequency. Taken together, these results reveal a novel role for IR signaling in the regulation of dendritic spine formation and excitatory synapse development in hippocampal neurons through activation of the PI3K/Akt/mTOR and Rac1 signaling pathways. (C) 2011 Elsevier Ltd. All rights reserved.