Insulin promotes dendritic spine and synapse formation by the PI3K/Akt/mTOR and Rac1 signaling pathways

Cheng Che Lee, Chiung Chun Huang, Kuei Sen Hsu

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)867-879
Number of pages13
JournalNeuropharmacology
Volume61
Issue number4
DOIs
Publication statusPublished - 2011 Sep 1

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Phosphatidylinositol 3-Kinase
Dendritic Spines
Sirolimus
Synapses
Insulin
Insulin Receptor
Neuronal Plasticity
Excitatory Postsynaptic Potentials
Small Interfering RNA
Neurons
Blocking Antibodies
Monomeric GTP-Binding Proteins
Down-Regulation
Pharmacology
Staining and Labeling

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

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abstract = "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.",
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Insulin promotes dendritic spine and synapse formation by the PI3K/Akt/mTOR and Rac1 signaling pathways. / Lee, Cheng Che; Huang, Chiung Chun; Hsu, Kuei Sen.

In: Neuropharmacology, Vol. 61, No. 4, 01.09.2011, p. 867-879.

Research output: Contribution to journalArticle

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