title: Neuronal activity drives localized blood-brain-barrier transport of serum insulin-like growth factor-I into the CNS.
abstract: 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 neurovascular coupling. These messengers stimulate matrix metalloproteinase-9, leading to cleavage of the IGF binding protein-3 (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 proneurogenic effects of epilepsy, rehabilitatory effects of neural stimulation, and modulatory effects of blood flow on brain activity.
authors.affiliation: Cajal Institute, CSIC and CIBERNED, 28002 Madrid, Spain.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishijima
authors.forename: Joaquin
authors.initials: J
authors.lastname: Piriz
authors.forename: Sylvie
authors.initials: S
authors.lastname: Duflot
authors.forename: Ana M
authors.initials: AM
authors.lastname: Fernandez
authors.forename: Gema
authors.initials: G
authors.lastname: Gaitan
authors.forename: Ulises
authors.initials: U
authors.lastname: Gomez-Pinedo
authors.forename: Jose M Garcia
authors.initials: JM
authors.lastname: Verdugo
authors.forename: Felix
authors.initials: F
authors.lastname: Leroy
authors.forename: Hideaki
authors.initials: H
authors.lastname: Soya
authors.forename: Angel
authors.initials: A
authors.lastname: Nuñez
authors.forename: Ignacio
authors.initials: I
authors.lastname: Torres-Aleman
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics / Q000379:methods; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D001831:Body Temperature / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D018920:Coculture Techniques; D004076:Digoxigenin / Q000378:metabolism; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D042783:Endothelial Cells / Q000378:metabolism / Q000648:ultrastructure; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007839:Functional Laterality; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D017551:Microdialysis / Q000379:methods; D016253:Microscopy, Immunoelectron / Q000379:methods; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009434:Neural Pathways; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014738:Vibrissae / Q000294:innervation
chemical_list: D018691:Excitatory Amino Acid Antagonists; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D009419:Nerve Tissue Proteins; D018698:Glutamic Acid; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D020780:Matrix Metalloproteinase 9; D004076:Digoxigenin