Neuropsin cleaves EphB2 in the amygdala to control anxiety

Many individuals experience traumatic events, but some people seem relatively unaffected whereas others develop post-traumatic stress disorder. Now, work in mice has identified a possible cause for this variation between individuals. During stress, the serine protease neuropsin elicits plasticity in the amygdala by regulating EphB2/NMDA receptor interactions, inducing expression of the fear-related gene Fkbp5v. Mice lacking neuropsin do not exhibit the same dynamic plasticity in response to stress. These results underscore the importance of molecular pathways in the manifestation of complex behaviours such as anxiety, and point to Eph and NMDA receptors as possible therapeutic targets. 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.