title: Deleting IGF-1 receptor from forebrain neurons confers neuroprotection during stroke and upregulates endocrine somatotropin.
abstract: Insulin-like growth factors control numerous processes, namely somatic growth, metabolism and stress resistance, connecting this pathway to aging and age-related diseases. Insulin-like growth factor signaling also impacts on neurogenesis, neuronal survival and structural plasticity. Recent reports demonstrated that diminished insulin-like growth factor signaling confers increased stress resistance in brain and other tissues. To better understand the role of neuronal insulin-like growth factor signaling in neuroprotection, we inactivated insulin-like growth factor type-1-receptor in forebrain neurons using conditional Cre-LoxP-mediated gene targeting. We found that brain structure and function, including memory performance, were preserved in insulin-like growth factor receptor mutants, and that certain characteristics improved, notably synaptic transmission in hippocampal neurons. To reveal stress-related roles of insulin-like growth factor signaling, we challenged the brain using a stroke-like insult. Importantly, when charged with hypoxia-ischemia, mutant brains were broadly protected from cell damage, neuroinflammation and cerebral edema. We also found that in mice with insulin-like growth factor receptor knockout specifically in forebrain neurons, a substantial systemic upregulation of growth hormone and insulin-like growth factor-I occurred, which was associated with significant somatic overgrowth. Collectively, we found strong evidence that blocking neuronal insulin-like growth factor signaling increases peripheral somatotropic tone and simultaneously protects the brain against hypoxic-ischemic injury, findings that may contribute to developing new therapeutic concepts preventing the disabling consequences of stroke.
authors.affiliation: 1 INSERM Research Center UMR938, Paris, France.|2 Sorbonne Universités, UPMC - Université Pierre et Marie Curie, Paris, France.
authors.forename: C Daniel
authors.initials: CD
authors.lastname: De Magalhaes Filho
authors.affiliation: 1 INSERM Research Center UMR938, Paris, France.|2 Sorbonne Universités, UPMC - Université Pierre et Marie Curie, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Kappeler
authors.affiliation: 3 INRA UMR85, Nouzilly, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dupont
authors.affiliation: 1 INSERM Research Center UMR938, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Solinc
authors.affiliation: 4 INSERM U1141, Paris, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Villapol
authors.affiliation: 2 Sorbonne Universités, UPMC - Université Pierre et Marie Curie, Paris, France.|5 INSERM UMR1130, Neurosciences, Institut de Biologie Paris-Seine, Paris, France.|6 CNRS UMR8246, Neurosciences, Institut de Biologie Paris-Seine, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Denis
authors.affiliation: 2 Sorbonne Universités, UPMC - Université Pierre et Marie Curie, Paris, France.|5 INSERM UMR1130, Neurosciences, Institut de Biologie Paris-Seine, Paris, France.|6 CNRS UMR8246, Neurosciences, Institut de Biologie Paris-Seine, Paris, France.
authors.forename: Marika
authors.initials: M
authors.lastname: Nosten-Bertrand
authors.affiliation: 7 Centre de Psychiatrie et Neurosciences, UMR894, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Billard
authors.affiliation: 1 INSERM Research Center UMR938, Paris, France.|2 Sorbonne Universités, UPMC - Université Pierre et Marie Curie, Paris, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Blaise
authors.affiliation: 2 Sorbonne Universités, UPMC - Université Pierre et Marie Curie, Paris, France.|5 INSERM UMR1130, Neurosciences, Institut de Biologie Paris-Seine, Paris, France.|6 CNRS UMR8246, Neurosciences, Institut de Biologie Paris-Seine, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Tronche
authors.affiliation: 2 Sorbonne Universités, UPMC - Université Pierre et Marie Curie, Paris, France.|5 INSERM UMR1130, Neurosciences, Institut de Biologie Paris-Seine, Paris, France.|6 CNRS UMR8246, Neurosciences, Institut de Biologie Paris-Seine, Paris, France.|8 Department of Psychiatry, Douglas Mental Health Research Center, McGill University, Montreal, Quebec, Canada.
authors.forename: Bruno
authors.initials: B
authors.lastname: Giros
authors.affiliation: 4 INSERM U1141, Paris, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Charriaut-Marlangue
authors.affiliation: 1 INSERM Research Center UMR938, Paris, France.|2 Sorbonne Universités, UPMC - Université Pierre et Marie Curie, Paris, France.
authors.forename: Saba
authors.initials: S
authors.lastname: Aïd
authors.affiliation: 1 INSERM Research Center UMR938, Paris, France.|2 Sorbonne Universités, UPMC - Université Pierre et Marie Curie, Paris, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Bouc
authors.affiliation: 1 INSERM Research Center UMR938, Paris, France.|2 Sorbonne Universités, UPMC - Université Pierre et Marie Curie, Paris, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Holzenberger
mesh_terms: D000818:Animals; D005260:Female; D017353:Gene Deletion; D013006:Growth Hormone / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D000066829:Neuroprotection; D016548:Prosencephalon / Q000378:metabolism / Q000473:pathology*; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D020521:Stroke / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation
chemical_list: D013006:Growth Hormone; D017526:Receptor, IGF Type 1
keywords: Cerebral edema; hypoxia-ischemia; insulin-like growth factor; neuroinflammation; neuroprotection