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.


  1. 1

    Giagtzoglou, N., Ly, C.V. & Bellen, H.J. Cell adhesion, the backbone of the synapse: “vertebrate” and “invertebrate” perspectives. Cold Spring Harb. Perspect. Biol. 1, a003079 (2009).

    Article  Google Scholar 

  2. 2

    Shapiro, L., Love, J. & Colman, D.R. Adhesion molecules in the nervous system: structural insights into function and diversity. Annu. Rev. Neurosci. 30, 451–474 (2007).

    CAS  Article  Google Scholar 

  3. 3

    Dalva, M.B., McClelland, A.C. & Kayser, M.S. Cell adhesion molecules: signaling functions at the synapse. Nat. Rev. Neurosci. 8, 206–220 (2007).

    CAS  Article  Google Scholar 

  4. 4

    Parrish, J.Z., Emoto, K., Kim, M.D. & Jan, Y.N. Mechanisms that regulate establishment, maintenance and remodeling of dendritic fields. Annu. Rev. Neurosci. 30, 399–423 (2007).

    CAS  Article  Google Scholar 

  5. 5

    Südhof, T.C. Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455, 903–911 (2008).

    Article  Google Scholar 

  6. 6

    Lin, Y.C. & Koleske, A.J. Mechanisms of synapse and dendrite maintenance and their disruption in psychiatric and neurodegenerative disorders. Annu. Rev. Neurosci. 33, 349–378 (2010).

    CAS  Article  Google Scholar 

  7. 7

    Sandi, C. Stress, cognitive impairment and cell adhesion molecules. Nat. Rev. Neurosci. 5, 917–930 (2004).

    CAS  Article  Google Scholar 

  8. 8

    Lupien, S.J., McEwen, B.S., Gunnar, M.R. & Heim, C. Effects of stress throughout the lifespan on the brain, behavior and cognition. Nat. Rev. Neurosci. 10, 434–445 (2009).

    CAS  Article  Google Scholar 

  9. 9

    Rice, C.J., Sandman, C.A., Lenjavi, M.R. & Baram, T.Z. A novel mouse model for acute and long-lasting consequences of early life stress. Endocrinology 149, 4892–4900 (2008).

    CAS  Article  Google Scholar 

  10. 10

    Brunson, K.L. et al. Mechanisms of late-onset cognitive decline after early-life stress. J. Neurosci. 25, 9328–9338 (2005).

    CAS  Article  Google Scholar 

  11. 11

    Wang, X.D. et al. Forebrain CRF1 modulates early-life stress–programmed cognitive deficits. J. Neurosci. 31, 13625–13634 (2011).

    CAS  Article  Google Scholar 

  12. 12

    Ivy, A.S. et al. Hippocampal dysfunction and cognitive impairments provoked by chronic early-life stress involve excessive activation of CRH receptors. J. Neurosci. 30, 13005–13015 (2010).

    CAS  Article  Google Scholar 

  13. 13

    Wang, X.D. et al. Forebrain CRHR1 deficiency attenuates chronic stress–induced cognitive deficits and dendritic remodeling. Neurobiol. Dis. 42, 300–310 (2011).

    CAS  Article  Google Scholar 

  14. 14

    Mizoguchi, A. et al. Nectin: an adhesion molecule involved in formation of synapses. J. Cell Biol. 156, 555–565 (2002).

    CAS  Article  Google Scholar 

  15. 15

    Majima, T. et al. Involvement of afadin in the formation and remodeling of synapses in the hippocampus. Biochem. Biophys. Res. Commun. 385, 539–544 (2009).

    CAS  Article  Google Scholar 

  16. 16

    Honda, T. et al. Involvement of nectins in the formation of puncta adherentia junctions and the mossy fiber trajectory in the mouse hippocampus. Mol. Cell Neurosci. 31, 315–325 (2006).

    CAS  Article  Google Scholar 

  17. 17

    Togashi, H. et al. Interneurite affinity is regulated by heterophilic nectin interactions in concert with the cadherin machinery. J. Cell Biol. 174, 141–151 (2006).

    CAS  Article  Google Scholar 

  18. 18

    Lim, S.T., Lim, K.C., Giuliano, R.E. & Federoff, H.J. Temporal and spatial localization of nectin-1 and l-afadin during synaptogenesis in hippocampal neurons. J. Comp. Neurol. 507, 1228–1244 (2008).

    CAS  Article  Google Scholar 

  19. 19

    Beaudoin, G.M. III et al. Afadin, a Ras/Rap effector that controls cadherin function, promotes spine and excitatory synapse density in the hippocampus. J. Neurosci. 32, 99–110 (2012).

    CAS  Article  Google Scholar 

  20. 20

    Suzuki, K. et al. Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia. Nat. Genet. 25, 427–430 (2000).

    CAS  Article  Google Scholar 

  21. 21

    Thompson, C.L. et al. Genomic anatomy of the hippocampus. Neuron 60, 1010–1021 (2008).

    CAS  Article  Google Scholar 

  22. 22

    Chen, Y., Dubé, C.M., Rice, C.J. & Baram, T.Z. Rapid loss of dendritic spines after stress involves derangement of spine dynamics by corticotropin-releasing hormone. J. Neurosci. 28, 2903–2911 (2008).

    CAS  Article  Google Scholar 

  23. 23

    Conrad, C.D. What is the functional significance of chronic stress–induced CA3 dendritic retraction within the hippocampus? Behav. Cogn. Neurosci. Rev. 5, 41–60 (2006).

    Article  Google Scholar 

  24. 24

    Müller, M.B. et al. Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nat. Neurosci. 6, 1100–1107 (2003).

    Article  Google Scholar 

  25. 25

    Lu, A. et al. Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behavior. Mol. Psychiatry 13, 1028–1042 (2008).

    CAS  Article  Google Scholar 

  26. 26

    Refojo, D. et al. Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1. Science 333, 1903–1907 (2011).

    CAS  Article  Google Scholar 

  27. 27

    Kühne, C. et al. Visualizing corticotropin-releasing hormone receptor type 1 expression and neuronal connectivities in the mouse using a novel multifunctional allele. J. Comp. Neurol. 520, 3150–3180 (2012).

    Article  Google Scholar 

  28. 28

    Srivastava, D.P. et al. Afadin is required for maintenance of dendritic structure and excitatory tone. J. Biol. Chem. 287, 35964–35974 (2012).

    CAS  Article  Google Scholar 

  29. 29

    Xie, Z. et al. Coordination of synaptic adhesion with dendritic spine remodeling by AF-6 and kalirin-7. J. Neurosci. 28, 6079–6091 (2008).

    CAS  Article  Google Scholar 

  30. 30

    Chen, Y. et al. Impairment of synaptic plasticity by the stress mediator CRH involves selective destruction of thin dendritic spines via RhoA signaling. Mol. Psychiatry 18, 485–496 (2013).

    CAS  Article  Google Scholar 

  31. 31

    Maras, P.M. & Baram, T.Z. Sculpting the hippocampus from within: stress, spines and CRH. Trends Neurosci. 35, 315–324 (2012).

    CAS  Article  Google Scholar 

  32. 32

    Chen, Y., Andres, A.L., Frotscher, M. & Baram, T.Z. Tuning synaptic transmission in the hippocampus by stress: the CRH system. Front. Cell Neurosci. 6, 13 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Refojo, D. et al. Corticotropin-releasing hormone activates ERK1/2 MAPK in specific brain areas. Proc. Natl. Acad. Sci. USA 102, 6183–6188 (2005).

    CAS  Article  Google Scholar 

  34. 34

    Schrick, C. et al. N-cadherin regulates cytoskeletally associated IQGAP1/ERK signaling and memory formation. Neuron 55, 786–798 (2007).

    CAS  Article  Google Scholar 

  35. 35

    Tan, Z.J., Peng, Y., Song, H.L., Zheng, J.J. & Yu, X. N-cadherin–dependent neuron-neuron interaction is required for the maintenance of activity-induced dendrite growth. Proc. Natl. Acad. Sci. USA 107, 9873–9878 (2010).

    CAS  Article  Google Scholar 

  36. 36

    Arikkath, J. & Reichardt, L.F. Cadherins and catenins at synapses: roles in synaptogenesis and synaptic plasticity. Trends Neurosci. 31, 487–494 (2008).

    CAS  Article  Google Scholar 

  37. 37

    von Wolff, G. et al. Voltage-sensitive dye imaging demonstrates an enhancing effect of corticotropin-releasing hormone on neuronal activity propagation through the hippocampal formation. J. Psychiatr. Res. 45, 256–261 (2011).

    Article  Google Scholar 

  38. 38

    Li, Y.W. et al. Receptor occupancy of nonpeptide corticotropin-releasing factor 1 antagonist DMP696: correlation with drug exposure and anxiolytic efficacy. J. Pharmacol. Exp. Ther. 305, 86–96 (2003).

    CAS  Article  Google Scholar 

  39. 39

    Wang, X.D. et al. Early-life stress-induced anxiety-related behavior in adult mice partially requires forebrain corticotropin-releasing hormone receptor 1. Eur. J. Neurosci. 36, 2360–2367 (2012).

    Article  Google Scholar 

  40. 40

    Wagner, K.V. et al. Homer1 mediates acute stress-induced cognitive deficits in the dorsal hippocampus. J. Neurosci. 33, 3857–3864 (2013).

    CAS  Article  Google Scholar 

  41. 41

    Schmidt, M.V. et al. Tumor suppressor down-regulated in renal cell carcinoma 1 (DRR1) is a stress-induced actin bundling factor that modulates synaptic efficacy and cognition. Proc. Natl. Acad. Sci. USA 108, 17213–17218 (2011).

    CAS  Article  Google Scholar 

  42. 42

    Paxinos, G. & Watson, C. The Mouse Brain in Stereotaxic Coordinates (Academic Press, San Diego, CA, USA, 2001).

  43. 43

    Schmidt, M.V. et al. Individual stress vulnerability is predicted by short-term memory and AMPA receptor subunit ratio in the hippocampus. J. Neurosci. 30, 16949–16958 (2010).

    CAS  Article  Google Scholar 

  44. 44

    Wagner, K.V. et al. Differences in FKBP51 regulation following chronic social defeat stress correlate with individual stress sensitivity: influence of paroxetine treatment. Neuropsychopharmacology 37, 2797–2808 (2012).

    CAS  Article  Google Scholar 

  45. 45

    Heck, N., Betuing, S., Vanhoutte, P. & Caboche, J. A deconvolution method to improve automated 3D-analysis of dendritic spines: application to a mouse model of Huntington's disease. Brain Struct. Funct. 217, 421–434 (2012).

    Article  Google Scholar 

  46. 46

    Dumitriu, D., Rodriguez, A. & Morrison, J.H. High-throughput, detailed, cell-specific neuroanatomy of dendritic spines using microinjection and confocal microscopy. Nat. Protoc. 6, 1391–1411 (2011).

    CAS  Article  Google Scholar 

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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).

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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.

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Correspondence to Mathias V Schmidt.

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The authors declare no competing financial interests.

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Wang, X., Su, Y., 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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