Neurotoxicity Research

, Volume 16, Issue 3, pp 280–292

IGF-1 and pAKT Signaling Promote Hippocampal CA1 Neuronal Survival Following Injury to Dentate Granule Cells

  • Robert N. Wine
  • Christopher A. McPherson
  • G. Jean Harry
Article

Abstract

Insulin-like growth factor-1 (IGF-1) protects neurons from apoptosis and in vivo offers neuroprotective support to hippocampal CA1 pyramidal neurons following ischemia or seizure. IGF-1 signals through IGF-1 receptors activating phosphytidylinositol 3-kinase (PI3K)/Akt or pMAPK pathways. IGF-1 can be induced with injury and microglia and astrocytes may serve as a source of this neurotrophic factor to promote neuronal survival. An acute systemic injection of trimethyltin (TMT; 2 mg/kg, ip) to mice induces apoptosis of dentate granule neurons within 24 h and a differential response of microglia with ramified microglia present in the CA-1 region. Using this model, we studied the role of IGF-1 in the survival of CA-1 pyramidal neurons under conditions of altered synaptic input due to changes in the dentate gyrus. Within 24 h of injection, IGF-1 mRNA levels were elevated in the hippocampus and IGF-1 protein detected in both astrocytes and microglia. IGF-1 was redistributed within the CA-1 neurons corresponding with an increase in cytoplasmic pAkt, elevated PKBα/Akt protein levels, and a decrease in the antagonist, Rho. pMAPK was not detected in CA-1 neurons and ERK2 showed a transient decrease followed by a significant increase, suggesting a lack of recruitment of the pMAPK signaling pathway for neuronal survival. In mice deficient for IGF-1, a similar level of apoptosis was observed in dentate granule neurons as compared to wildtype; however, TMT induced a significant level CA-1 neuronal death, further supporting a role for IGF-1 in the survival of CA-1 neurons.

Keywords

Microglia Hippocampus Pyramidal neurons Trimethyltin IGF-1 pAkt Seizure 

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Robert N. Wine
    • 1
  • Christopher A. McPherson
    • 1
  • G. Jean Harry
    • 1
  1. 1.Laboratory of Molecular ToxicologyNational Institute of Environmental Health Sciences, National Institutes of HealthResearch Triangle ParkUSA

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