Neuronal Activity Drives Localized Blood-brain-barrier Transport of Serum Insulin-like Growth Factor-i into the Central Nervous System

Upon entry into the central nervous system (CNS), serum insulin-like growth factor-1 (IGF-I) modulates neuronal growth, survival and excitability. Yet mechanisms that trigger IGF-I entry across the blood-brain barrier remain unclear. We show that neuronal activity elicited by electrical, sensory or behavioral stimulation increases IGF-I input in activated regions. Entrance of serum IGF-I is triggered by diffusible messengers (i.e. ATP, arachidonic acid derivatives) released during neuro-vascular coupling. These messengers stimulate matrix metalloproteinase-9, leading to cleavage of the IGF binding protein-3 *Manuscript Click here to view linked References 2 (IGFBP-3). Cleavage of IGFBP-3 allows the passage of serum IGF-I into the CNS through an interaction with the endothelial transporter lipoprotein related receptor 1. Activity-dependent entrance of serum IGF-I into the CNS may help to explain disparate observations such as pro-neurogenic effects of epilepsy, rehabilitatory effects of neural stimulation and modulatory effects of blood flow on brain activity.