Both ex vivo and in vivo studies have demonstrated the capacity of IGF-1 to stimulate neuronal differentiation. Studies demonstrating IGF-1 stimulation of neuritic outgrowth were among the first showing IGF-1 actions on neural cells26. Later IGF-1 was shown to increase dendrite growth in cultured neonatal Purkinje cells27 and to increase the number of pyramidal cell dendrites and their branching in somatosensory cortical explants28. In cultured hippocampal neurons, IGF-1 stimulates the assembly of axonal growth cones29, 30 and the establishment of neuronal polarity10. IGF-1R knock-out mice die shortly after birth and have serious defects in central nervous system development31. In humans, both homozygous and heterozygous mutations of the IGF-1R have been described and several developmental defects are consistently found in these patients, including microcephaly and cortical layer disorganization32. The PI3K pathway is also essential for neuronal polarization in hippocampal neurons in culture11, 17.