Circulating Insulin-like Growth Factor I Regulates Its Receptor in the Brain of Male Mice

The role of insulin-like growth factor I (IGF-I) and its receptor (IGF-IR) in brain pathology is still unclear. Thus, either reduction of IGF-IR or treatment with IGF-I, two apparently opposite actions, has proven beneficial in brain diseases such as Alzheimer´s dementia (AD). A possible explanation of this discrepancy is that IGF-I down-regulates brain IGF-IR levels, as previously seen in a mouse AD model. We now explored whether under normal conditions IGF-I modulates its receptor. We first observed that in vitro, IGF-I reduced IGF-IR mRNA levels in all types of brain cells including neurons, astrocytes, microglia, endothelial cells, and oligodendrocytes. IGF-I also inhibited its own expression in neurons and brain endothelium. Next, we analyzed in vivo actions of IGF-I. As serum IGF-I can enter the brain, we injected mice with IGF-I intraperitoneously. As soon as one hour after injection, decreased hippocampal IGF-I levels were observed, followed by increased IGF-I and IGF-IR mRNAs six hours later. As environmental enrichment (EE) stimulates the entrance of serum IGF-I into the brain, we analyzed whether a physiological entrance of IGF-I also produced changes in brain IGF-IR. Stimulation of IGF-IR by EE triggered a gradual decrease in hippocampal IGF-I levels. After six hours of EE exposure, IGF-I levels reached a significant decrease in parallel with increased IGF-IR expression. After longer times, IGF-IR mRNA levels returned to baseline. Thus, under non-pathological conditions, IGF-I regulates brain IGF-IR. Because baseline IGF-IR levels are rapidly restored, a tight control of brain IGF-IR expression seems to operate under physiological conditions.