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J Cereb Blood Flow Metab. 2017 Feb;37(2):396-412. doi: 10.1177/0271678X15626718. Epub 2016 Jul 20.

Deleting IGF-1 receptor from forebrain neurons confers neuroprotection during stroke and upregulates endocrine somatotropin.

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1 INSERM Research Center UMR938, Paris, France.
2 Sorbonne Universités, UPMC - Université Pierre et Marie Curie, Paris, France.
3 INRA UMR85, Nouzilly, France.
4 INSERM U1141, Paris, France.
5 INSERM UMR1130, Neurosciences, Institut de Biologie Paris-Seine, Paris, France.
6 CNRS UMR8246, Neurosciences, Institut de Biologie Paris-Seine, Paris, France.
7 Centre de Psychiatrie et Neurosciences, UMR894, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
8 Department of Psychiatry, Douglas Mental Health Research Center, McGill University, Montreal, Quebec, Canada.


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.


Cerebral edema; hypoxia-ischemia; insulin-like growth factor; neuroinflammation; neuroprotection

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