Nectin-3 links CRHR1 signaling to stress-induced memory deficits and spine loss

Nat Neurosci. 2013 Jun;16(6):706-13. doi: 10.1038/nn.3395. Epub 2013 May 5.


Stress impairs cognition via corticotropin-releasing hormone receptor 1 (CRHR1), but the molecular link between abnormal CRHR1 signaling and stress-induced cognitive impairments remains unclear. We investigated whether the cell adhesion molecule nectin-3 is required for the effects of CRHR1 on cognition and structural remodeling after early-life stress exposure. Postnatally stressed adult mice had decreased hippocampal nectin-3 levels, which could be attenuated by CRHR1 inactivation and mimicked by corticotropin-releasing hormone (CRH) overexpression in forebrain neurons. Acute stress dynamically reduced hippocampal nectin-3 levels, which involved CRH-CRHR1, but not glucocorticoid receptor, signaling. Suppression of hippocampal nectin-3 caused spatial memory deficits and dendritic spine loss, whereas enhancing hippocampal nectin-3 expression rescued the detrimental effects of early-life stress on memory and spine density in adulthood. Our findings suggest that hippocampal nectin-3 is necessary for the effects of stress on memory and structural plasticity and indicate that the CRH-CRHR1 system interacts with the nectin-afadin complex to mediate such effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • Cell Adhesion Molecules / antagonists & inhibitors
  • Cell Adhesion Molecules / physiology*
  • Corticotropin-Releasing Hormone / physiology
  • Dendritic Spines / metabolism*
  • Dendritic Spines / pathology
  • Down-Regulation / genetics
  • Female
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Hippocampus / physiopathology*
  • Male
  • Memory / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Nectins
  • Prosencephalon / pathology
  • Prosencephalon / physiology
  • Receptors, Corticotropin-Releasing Hormone / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Stress, Psychological* / metabolism
  • Stress, Psychological* / physiopathology
  • Up-Regulation / genetics


  • Cell Adhesion Molecules
  • Nectin3 protein, mouse
  • Nectins
  • Receptors, Corticotropin-Releasing Hormone
  • CRF receptor type 1
  • Corticotropin-Releasing Hormone