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

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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.

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This research was funded by the Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health.

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  1. Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, MD C1-04, Research Triangle Park, NC, 27709, USA

    Robert N. Wine, Christopher A. McPherson & G. Jean Harry

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Wine, R.N., McPherson, C.A. & Harry, G.J. IGF-1 and pAKT Signaling Promote Hippocampal CA1 Neuronal Survival Following Injury to Dentate Granule Cells. Neurotox Res 16, 280–292 (2009). https://doi.org/10.1007/s12640-009-9060-y

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