Insulin-like growth factor-I gene therapy increases hippocampal neurogenesis, astrocyte branching and improves spatial memory in female aging rats

• Published in: The European journal of neuroscience 2016-08, Vol.44 (4), p.2120-2128
• Main Authors: Pardo, Joaquín, Uriarte, Maia, Cónsole, Gloria M., Reggiani, Paula C., Outeiro, Tiago F., Morel, Gustavo R., Goya, Rodolfo G.
• Format: Article
• Language: English
• Subjects: aging; Animals; Astrocytes - metabolism; Barnes maze; Cognition - physiology; Cognition Disorders - genetics; Cognition Disorders - metabolism; Cognition Disorders - therapy; Female; gene therapy; Genetic Therapy; hippocampal morphology; Hippocampus - cytology; Hippocampus - metabolism; IGF-I; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Memory Disorders - genetics; Memory Disorders - therapy; Neurogenesis - physiology; Rats, Sprague-Dawley; spatial memory; Spatial Memory - physiology
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.13278

In rats, learning and memory performance decline during aging, which makes this rodent species a suitable model to evaluate therapeutic strategies of potential value for correcting age‐related cognitive deficits. Some of these strategies involve neurotrophic factors like insulin‐like growth factor‐I (IGF‐I), a powerful neuroprotective molecule in the brain. Here, we implemented 18‐day long intracerebroventricular (ICV) IGF‐I gene therapy in 28 months old Sprague–Dawley female rats, and assessed spatial memory performance in the Barnes maze. We also studied hippocampal morphology using an unbiased stereological approach. Adenovectors expressing the gene for rat IGF‐I or the reporter DsRed were used. Cerebrospinal fluid (CSF) samples were taken and IGF‐I levels determined by radioimmunoassay. At the end of the study, IGF‐I levels in the CSF were significantly higher in the experimental group than in the DsRed controls. After treatment, the IGF‐I group showed a significant improvement in spatial memory accuracy as compared with DsRed counterparts. In the dentate gyrus (DG) of the hippocampus, the IGF‐I group showed a higher number of immature neurons than the DsRed controls. The treatment increased hippocampal astrocyte branching and reduced their number in the hippocampal stratum radiatum. We conclude that the ependymal route is an effective approach to increase CSF levels of IGF‐I and that this strategy improves the accuracy of spatial memory in aging rats. The favorable effect of the treatment on DG neurogenesis and astrocyte branching in the stratum radiatum may contribute to improving memory performance in aging rats. Intracerebroventricular (ICV) Insulin‐like growth factor I (IGF‐I) gene therapy improved spatial memory accuracy in old rats, as measured in the hippocampus‐dependent Barnes maze task. Gene therapy increased immature neuron number in the hippocampal dentate gyrus. Additionaly, astrocyte number decreased , whereas their proximal branching increased in the hippocampal stratum radiatum. We conclude that ICV IGF‐I gene therapy is effective to reverse cognitive dysfunction in the aging rat.