Antagonism of brain insulin-like growth factor-1 receptors blocks estradiol effects on memory and levels of hippocampal synaptic proteins in ovariectomized rats

• Published in: Psychopharmacology 2014-03, Vol.231 (5), p.899-907
• Main Authors: Nelson, Britta S., Springer, Rachel C., Daniel, Jill M.
• Format: Article
• Language: English
• Subjects: Analysis; Animal memory; Animals; Biomedical and Life Sciences; Biomedicine; Cognition & reasoning; Disks Large Homolog 4 Protein; Estradiol; Estradiol - pharmacology; Estrogen Antagonists - pharmacology; Estrogens; Female; Growth factor receptors; Guanylate Kinases - metabolism; Hippocampus - drug effects; Hippocampus - metabolism; Insulin-like growth factors; Intracellular Signaling Peptides and Proteins - metabolism; Maze Learning - drug effects; Membrane Proteins - metabolism; Memory; Memory - drug effects; Microfilament Proteins - metabolism; Nerve Tissue Proteins - metabolism; Neurosciences; Oligopeptides - pharmacology; Original Investigation; Pharmacology/Toxicology; Physiological aspects; Proteins; Psychiatry; Psychopharmacology; Rats; Rats, Long-Evans; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, IGF Type 1 - metabolism; Spatial Navigation - drug effects; Synapses - drug effects; Synapses - metabolism; Synaptophysin - metabolism
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-013-3310-7

Rationale Treatment with estradiol, the primary estrogen produced by the ovaries, enhances hippocampus-dependent spatial memory and increases levels of hippocampal synaptic proteins in ovariectomized rats. Increasing evidence indicates that the ability of estradiol to impact the brain and behavior is dependent upon its interaction with insulin-like growth factor-1 (IGF-1). Objective The goal of the current experiment was to test the hypothesis that the ability of estradiol to impact hippocampus-dependent memory and levels of hippocampal synaptic proteins is dependent on its interaction with IGF-1. Methods Adult rats were ovariectomized and implanted with estradiol or control capsules and trained on a radial-maze spatial memory task. After training, rats were implanted with intracerebroventricular cannulae attached to osmotic minipumps (flow rate 0.15 μl/h). Half of each hormone treatment group received continuous delivery of JB1 (300 μg/ml), an IGF-1 receptor antagonist, and half received delivery of aCSF vehicle. Rats were tested on trials in the radial-arm maze during which delays were imposed between the fourth and fifth arm choices. Hippocampal levels of synaptic proteins were measured by western blotting. Results Estradiol treatment resulted in significantly enhanced memory. JB1 blocked that enhancement. Estradiol treatment resulted in significantly increased hippocampal levels of postsynaptic density protein 95 (PSD-95), spinophilin, and synaptophysin. JB1 blocked the estradiol-induced increase of PSD-95 and spinophilin and attenuated the increase of synaptophysin. Conclusions Results support a role for IGF-1 receptor activity in estradiol-induced enhancement of spatial memory that may be dependent on changes in synapse structure in the hippocampus brought upon by estradiol/IGF-1 interactions.