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

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


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.

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

MeSH terms

  • Animals
  • Female
  • Gene Deletion*
  • Growth Hormone / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotection*
  • Prosencephalon / metabolism
  • Prosencephalon / pathology*
  • Receptor, IGF Type 1 / genetics*
  • Stroke / genetics*
  • Stroke / metabolism
  • Stroke / pathology*
  • Up-Regulation


  • Growth Hormone
  • Receptor, IGF Type 1