PMID- 21683721
OWN - NLM
STAT- MEDLINE
DCOM- 20120525
LR  - 20220309
IS  - 1873-7064 (Electronic)
IS  - 0028-3908 (Linking)
VI  - 61
IP  - 4
DP  - 2011 Sep
TI  - Insulin promotes dendritic spine and synapse formation by the PI3K/Akt/mTOR and 
      Rac1 signaling pathways.
PG  - 867-79
LID - 10.1016/j.neuropharm.2011.06.003 [doi]
AB  - 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.
CI  - Copyright (c) 2011 Elsevier Ltd. All rights reserved.
FAU - Lee, Cheng-Che
AU  - Lee CC
AD  - Department of Pharmacology, College of Medicine, National Cheng Kung University, 
      Tainan, Taiwan.
FAU - Huang, Chiung-Chun
AU  - Huang CC
FAU - Hsu, Kuei-Sen
AU  - Hsu KS
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110612
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - 0 (Insulin)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.10.1 (Receptor, Insulin)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.1.- (Rac1 protein, rat)
RN  - EC 3.6.5.2 (rac1 GTP-Binding Protein)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Cells, Cultured
MH  - Dendritic Spines/drug effects/*physiology
MH  - Hippocampus/cytology/metabolism/physiology
MH  - Insulin/pharmacology/*physiology
MH  - Phosphatidylinositol 3-Kinase/*biosynthesis
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors/*biosynthesis
MH  - Rats
MH  - Receptor, Insulin/agonists/*physiology
MH  - Signal Transduction/drug effects/physiology
MH  - Synapses/drug effects/*physiology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*biosynthesis
MH  - rac1 GTP-Binding Protein/antagonists & inhibitors/*biosynthesis
EDAT- 2011/06/21 06:00
MHDA- 2012/05/26 06:00
CRDT- 2011/06/21 06:00
PHST- 2011/01/19 00:00 [received]
PHST- 2011/05/12 00:00 [revised]
PHST- 2011/06/02 00:00 [accepted]
PHST- 2011/06/21 06:00 [entrez]
PHST- 2011/06/21 06:00 [pubmed]
PHST- 2012/05/26 06:00 [medline]
AID - S0028-3908(11)00239-5 [pii]
AID - 10.1016/j.neuropharm.2011.06.003 [doi]
PST - ppublish
SO  - Neuropharmacology. 2011 Sep;61(4):867-79. doi: 10.1016/j.neuropharm.2011.06.003. 
      Epub 2011 Jun 12.