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



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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Figure 1: Regulation of hippocampal nectin-3 expression by stress and the involvement of CRH-CRHR1 signaling.
Figure 2: Regulation of hippocampal nectin-3 by CRH-CRHR1 signaling.
Figure 3: Colocalization of CRHR1 and nectin-3 in hippocampal CA1 pyramidal neurons.
Figure 4: Hippocampal nectin-3 knockdown impaired long-term spatial memory.
Figure 5: Nectin-3 knockdown reduced dendritic spine density in CA3 pyramidal neurons.
Figure 6: Hippocampal nectin-3 overexpression reversed early-life stress–induced cognitive deficits.
Figure 7: Nectin-3 overexpression rescued early-life stress–evoked spine loss and spine volume changes.
Figure 8: Modulation of L-afadin levels by CRH-CRHR1 signaling and nectin-3.


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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).

Author information




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.

Corresponding author

Correspondence to Mathias V Schmidt.

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The authors declare no competing financial interests.

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Wang, XD., Su, YA., Wagner, K. et al. Nectin-3 links CRHR1 signaling to stress-induced memory deficits and spine loss. Nat Neurosci 16, 706–713 (2013).

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