A Key Role of Insulin Receptors in Memory

Since the discovery of insulin in 1922 (1), the skeletal muscle, adipose tissue, and liver are traditionally regarded as key insulin-sensitive organs (2). Evidence of insulin actions in the brain emerged more recently, approximately 35 years ago, with studies showing that the hypothalamic actions of insulin regulate peripheral energy homeostasis (reviewed in [3]). Interestingly, insulin receptors were also detected in high densities in other brain regions (4), suggesting that insulin’s role in the central nervous system (CNS) extends beyond hypothalamic control of energy homeostasis. The hippocampus, a brain region key to memory and learning, was found to present particularly high levels of insulin receptors, suggesting that insulin could play a role in synaptic plasticity mechanisms and memory formation in rodents and humans. Indeed, studies using in vitro and in vivo experimental models indicated that insulin regulates neuronal survival, acts as a growth factor, and regulates circuit function and plasticity (reviewed in [5]). In cultured hippocampal neurons, insulin receptors present a punctate dendritic distribution that is consistent with the presence of insulin receptors at synaptic compartments (6). In harmony with the proposed role of insulin signaling in cognition, intranasal insulin treatment—a method achieving direct CNS delivery of insulin without invasiveness or major complications (7)—improves memory in healthy adults, without changing blood levels of insulin or glucose (reviewed in [8]). While these recent …