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

Nature Neuroscience volume 16, pages 706713 (2013) | Download Citation

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Abstract

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.

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Acknowledgements

We are grateful to D. Harbich and B. Schmid for technical assistance. This work was supported by the European Community's Seventh Framework Program (FP7, Project No. 201600), the Bundesministerium für Bildung und Forschung within the framework of the NGFN-Plus (FKZ: 01GS08151 and 01GS08155) and by the Initiative and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Health in an Ageing Society (HA-215).

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Author notes

    • Xiao-Dong Wang
    •  & Yun-Ai Su

    Present address: Institute of Mental Health, Peking University, Beijing, China, Key Laboratory for Mental Health, Ministry of Health (Peking University), Beijing, China.

Affiliations

  1. Max Planck Institute of Psychiatry, Munich, Germany.

    • Xiao-Dong Wang
    • , Yun-Ai Su
    • , Klaus V Wagner
    • , Charilaos Avrabos
    • , Sebastian H Scharf
    • , Jakob Hartmann
    • , Miriam Wolf
    • , Claudia Liebl
    • , Claudia Kühne
    • , Wolfgang Wurst
    • , Florian Holsboer
    • , Matthias Eder
    • , Jan M Deussing
    • , Marianne B Müller
    •  & Mathias V Schmidt
  2. Institute of Developmental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.

    • Wolfgang Wurst
  3. Technische Universität München, Lehrstuhl für Entwicklungsgenetik, Helmholtz Zentrum München, Neuherberg, Germany.

    • Wolfgang Wurst
  4. Deutsches Zentrum für Neurodegenerative Erkrankungen, Munich, Germany.

    • Wolfgang Wurst

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Contributions

X.-D.W. and M.V.S. designed the experiments. X.-D.W., Y.-A.S., K.V.W., C.A., S.H.S., J.H., M.W., C.L. and C.K. performed the experiments. X.-D.W., Y.-A.S., C.A. and M.W. analyzed the data. M.E., J.M.D., M.B.M. and M.V.S. supervised the experiments. X.-D.W., W.W., F.H., M.E., J.M.D., M.B.M. and M.V.S. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Mathias V Schmidt.

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DOI

https://doi.org/10.1038/nn.3395

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