Neuronal activity drives localized blood-brain-barrier transport of serum insulin-like growth factor-I into the CNS.
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.
Nishijima
Takeshi
T
Cajal Institute, CSIC and CIBERNED, 28002 Madrid, Spain.
Piriz
Joaquin
J
Duflot
Sylvie
S
Fernandez
Ana M
AM
Gaitan
Gema
G
Gomez-Pinedo
Ulises
U
Verdugo
Jose M Garcia
JM
Leroy
Felix
F
Soya
Hideaki
H
Nuñez
Angel
A
Torres-Aleman
Ignacio
I
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
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