Anxiety Control

Science Signaling  24 May 2011:
Vol. 4, Issue 174, pp. ec145
DOI: 10.1126/scisignal.4174ec145

Fear conditions individuals to remember and respond to danger; however, in some individuals, stress and trauma induce a generalized state of anxiety. In response to stress, neurons undergo remodeling, involving interactions between these cells and the extracellular matrix, which are facilitated by extracellular proteases. Noting that the Eph family of receptor tyrosine kinases modulate neuronal plasticity and are subject to cleavage by extracellular proteases, Attwood et al. investigated a role for Ephs in responding to stress. Immunohistochemical analysis of mouse brains showed that EphB2 and the serine protease neuropsin were abundant and colocalized in the amygdala, which processes memory and emotion. Experiments in a neuroblastoma cell line showed that EphB2, but not other Ephs, was cleaved by neuropsin to release an extracellular fragment of the receptor. EphB2 associates with the NMDA receptor, and coimmunoprecipitation assays showed that restraint stress reduced the amount of EphB2 that colocalized with the NR1 subunit of the NMDA receptor in the amygdala of wild-type, but not neuropsin-deficient, mice. Disruption of the EphB2-NR1 interaction resulted in the increased abundance of the protein Fkbp51, which promotes glucocorticoid receptor signaling. Whole-cell recordings in neurons from the basal amygdala showed that NMDA currents were lower in neuropsin-deficient mice than in wild-type mice. In addition, early long-term potentiation was impaired in neuropsin-deficient mice. Whereas stress increased the state of anxiety of wild-type mice, as measured by their responses in a maze test, neuropsin-deficient mice exhibited anxiety only after receiving injections of neuropsin. Together, these data suggest a mechanism whereby stress induces the cleavage of EphB2 by neuropsin, which results in enhanced NMDA receptor currents, the generation of Fkbp51, and the development of anxiety.

B. K. Attwood, J.-M. Bourgognon, S. Patel, M. Mucha, E. Schiavon, A. E. Skrzypiec, K. W. Young, S. Shiosaka, M. Korostynski, M. Piechota, R. Przewlocki, R. Pawlak, Neuropsin cleaves EphB2 in the amygdala to control anxiety. Nature 473, 372–375 (2011). [PubMed]