Chapter 12 INTERACTIONS OF INSULIN-LIKE GROWTH FACTOR-I AND ESTROGEN IN THE BRAIN Pablo Mendez\ Gloria Patricia Cardona-Gomez^ and Luis Miguel Garcia-Segura^ ^Instituto Cajal, C.S.LC, E-28002 Madrid, Spain; ^Group of Neuroscience, School of Medicine, University ofAntioquia, PO Box 1226 Medellin, Colombia Key words: Estradiol; gonadotrophins; IGF-I; neuronal development; neuroprotection; synaptic plasticity. 1. INTRODUCTION Insulin-like growth factor exerts different effects on the development and plasticity of the nervous system and is a potent neuroprotectant (see Chapters 8 and 10). As in other organs, the actions of IGF-I in the nervous system may be affected by the interaction with other molecules. In the brain, these include neurotransmitters, neuromodulators, hormones and other growth factors. For instance, growth hormone regulates IGF-I expression in the brain in an anatomically specific manner^ and leukemia inhibitory factor has been shown to regulate IGF-I levels in peripheral nerves^. The cross-talk between IGF-I intracellular signaling with the signaling pathways of other factors may also play an important role in the actions of IGF-I in the nervous system. This is the case of the interaction of IGF-I and nerve growth factor (NGF) in peripheral nerves, where the phosphatidylinositol-3 kinase (PI3K)- Akt-glycogen synthase kinase 3 (GSK3) pathway seems to underlie the synergism of these two factors on axonal growth^. Neurotransmitters, such as glutamate, may affect the actions of IGF-I in the brain by interfering with IGF-I receptor signaling. Recently it has been shown that glutamate at high