title: Neuropsin cleaves EphB2 in the amygdala to control anxiety.
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 interface. 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.
authors.affiliation: Department of Cell Physiology and Pharmacology, University of Leicester, University Road, Leicester LE1 9HN, UK.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Attwood
authors.forename: Julie-Myrtille
authors.initials: JM
authors.lastname: Bourgognon
authors.forename: Satyam
authors.initials: S
authors.lastname: Patel
authors.forename: Mariusz
authors.initials: M
authors.lastname: Mucha
authors.forename: Emanuele
authors.initials: E
authors.lastname: Schiavon
authors.forename: Anna E
authors.initials: AE
authors.lastname: Skrzypiec
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Young
authors.forename: Sadao
authors.initials: S
authors.lastname: Shiosaka
authors.forename: Michal
authors.initials: M
authors.lastname: Korostynski
authors.forename: Marcin
authors.initials: M
authors.lastname: Piechota
authors.forename: Ryszard
authors.initials: R
authors.lastname: Przewlocki
authors.forename: Robert
authors.initials: R
authors.lastname: Pawlak
mesh_terms: D000679:Amygdala / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism*; D001008:Anxiety Disorders / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D004553:Electric Conductivity; D005239:Fear; D005786:Gene Expression Regulation; D007610:Kallikreins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017774:Long-Term Potentiation; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D036183:Receptor, EphB2 / Q000737:chemistry / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D000099159:Tacrolimus Binding Protein 5
chemical_list: D007610:Kallikreins; D036183:Receptor, EphB2; D016194:Receptors, N-Methyl-D-Aspartate; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C409466:NR1 NMDA receptor; C114664:Prss19 protein, mouse