Abstract
A minority of individuals experiencing traumatic events develop anxiety disorders. The reason for the lack of correspondence between the prevalence of exposure to psychological trauma and the development of anxiety is unknown. Extracellular proteolysis contributes to fear-associated responses by facilitating neuronal plasticity at the neuron–matrix interface1,2,3,4. Here we show in mice that the serine protease neuropsin is critical for stress-related plasticity in the amygdala by regulating the dynamics of the EphB2–NMDA-receptor interaction, the expression of Fkbp5 and anxiety-like behaviour. Stress results in neuropsin-dependent cleavage of EphB2 in the amygdala causing dissociation of EphB2 from the NR1 subunit of the NMDA receptor and promoting membrane turnover of EphB2 receptors. Dynamic EphB2–NR1 interaction enhances NMDA receptor current, induces Fkbp5 gene expression and enhances behavioural signatures of anxiety. On stress, neuropsin-deficient mice do not show EphB2 cleavage and its dissociation from NR1 resulting in a static EphB2–NR1 interaction, attenuated induction of the Fkbp5 gene and low anxiety. The behavioural response to stress can be restored by intra-amygdala injection of neuropsin into neuropsin-deficient mice and disrupted by the injection of either anti-EphB2 antibodies or silencing the Fkbp5 gene in the amygdala of wild-type mice. Our findings establish a novel neuronal pathway linking stress-induced proteolysis of EphB2 in the amygdala to anxiety.
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Acknowledgements
This work was supported by a Medical Research Council Project Grant (G0500231/73852), and a Marie Curie Excellence Grant (MEXT-CT-2006-042265 from the European Commission) to R. Pawlak, a Medisearch Fellowship to B.K.A., the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grants-in-Aid, # 20300128) and Japan Science and Technology Agency (CREST program) to S.S., GENADDICT (LSHM-CT-2004-005166 from the European Commission) to R. Przewlocki, and NN405 274137 from the Ministry of Science and Higher Education of Poland to M.K. We are obliged to A. Kania, H. Castro and R. Fern for reagents. We are grateful to B. McEwen and A. Tobin for their comments on the manuscript and T. Gerdjikov, G. Mallucci and her laboratory members for advice.
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B.K.A., J.-M.B., S.P., M.M., E.S., A.E.S., K.W.Y. and R. Pawlak performed experiments and data analysis; R. Pawlak and B.K.A. designed most of the experiments; S.S. provided neuropsin−/− mice, suggestions and reagents; M.K., M.P. and R. Przewlocki performed bioinformatic analyses. R. Pawlak conceived the study and wrote the paper. All authors discussed the results and commented on the manuscript.
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Attwood, B., Bourgognon, JM., Patel, S. et al. Neuropsin cleaves EphB2 in the amygdala to control anxiety. Nature 473, 372–375 (2011). https://doi.org/10.1038/nature09938
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DOI: https://doi.org/10.1038/nature09938
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