IGF-1 and pAKT signaling promote hippocampal CA1 neuronal survival following injury to dentate granule cells.
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 PKBalpha/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.
Wine
Robert N
RN
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.
McPherson
Christopher A
CA
Harry
G Jean
GJ
D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000139:chemically induced / Q000150:complications / Q000473:pathology*; D056547:CA1 Region, Hippocampal / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D005452:Fluoresceins; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein; D006023:Glycoproteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism*; D009930:Organic Chemicals; D012640:Seizures / Q000139:chemically induced / Q000209:etiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014298:Trimethyltin Compounds / Q000633:toxicity
D005452:Fluoresceins; D005904:Glial Fibrillary Acidic Protein; D006023:Glycoproteins; D009419:Nerve Tissue Proteins; D009930:Organic Chemicals; D014298:Trimethyltin Compounds; C435731:fluoro jade; C528900:glial fibrillary astrocytic protein, mouse; C473590:isolectin B4-binding glycoprotein, mouse; C037718:trimethyltin hydroxide; D007334:Insulin-Like Growth Factor I; D051058:Oncogene Protein v-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D053148:Caspase 3