Endocrine, liver-derived IGF-I is of importance for spatial learning and memory in old mice

Abstract

IGF-I is a neuroprotective hormone, and neurodegenerative disorders, including Alzheimer’s disease, have been associated with decreased serum IGF-I concentration. In this study, IGF-I production was inactivated in the liver of adult mice (LI-IGF-I−/−), resulting in an approximately 80–85% reduction of circulating IGF-I concentrations. In young (6-month-old) mice there was no difference between the LI-IGF-I−/− and the control mice in spatial learning and memory as measured using the Morris water maze test. In old (aged 15 and 18 months) LI-IGF-I−/− mice, however, the acquisition of the spatial task was slower than in the controls. Furthermore, impaired spatial working as well as reference memory was observed in the old LI-IGF−/− mice. Histochemical analyses revealed an increase in dynorphin and enkephalin immunoreactivities but decreased mRNA levels in the hippocampus of old LI-IGF-I−/− mice. These mice also displayed astrocytosis and increased metabotropic glutamate receptor 7a-immunoreactivity. These neurochemical disturbances suggest synaptic dysfunction and early neurodegeneration in old LI-IGF-I−/− mice. The decline in serum IGF-I with increasing age may therefore be important for the age-related decline in memory function.