title: Chronic stress induces anxiety via an amygdalar intracellular cascade that impairs endocannabinoid signaling.
abstract: Collapse of endocannabinoid (eCB) signaling in the amygdala contributes to stress-induced anxiety, but the mechanisms of this effect remain unclear. eCB production is tied to the function of the glutamate receptor mGluR5, itself dependent on tyrosine phosphorylation. Herein, we identify a novel pathway linking eCB regulation of anxiety through phosphorylation of mGluR5. Mice lacking LMO4, an endogenous inhibitor of the tyrosine phosphatase PTP1B, display reduced mGluR5 phosphorylation, eCB signaling, and profound anxiety that is reversed by genetic or pharmacological suppression of amygdalar PTP1B. Chronically stressed mice exhibited elevated plasma corticosterone, decreased LMO4 palmitoylation, elevated PTP1B activity, reduced amygdalar eCB levels, and anxiety behaviors that were restored by PTP1B inhibition or by glucocorticoid receptor antagonism. Consistently, corticosterone decreased palmitoylation of LMO4 and its inhibition of PTP1B in neuronal cells. Collectively, these data reveal a stress-responsive corticosterone-LMO4-PTP1B-mGluR5 cascade that impairs amygdalar eCB signaling and contributes to the development of anxiety.
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, ON K1H8M5, Canada.
authors.forename: Zhaohong
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, ON K1H8M5, Canada.
authors.forename: Xun
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, ON K1H8M5, Canada.
authors.forename: Nihar R
authors.initials: NR
authors.lastname: Pandey
authors.affiliation: Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Departments of Cell Biology and Anatomy & Psychiatry, University of Calgary, Calgary, AB T2N4N1, Canada.
authors.forename: Haley A
authors.initials: HA
authors.lastname: Vecchiarelli
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, ON K1H8M5, Canada.
authors.forename: Chloe A
authors.initials: CA
authors.lastname: Stewart
authors.affiliation: Royal Ottawa Mental Health Centre, Ottawa, ON K1Z7K4, Canada; Department of Cellular and Molecular Medicine, Ottawa, ON K1H8M5, Canada.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Cellular and Molecular Medicine, Ottawa, ON K1H8M5, Canada.
authors.forename: Diane C
authors.initials: DC
authors.lastname: Lagace
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, Laboratory of Integrative Structural & Chemical Biology (iSCB), Aix-Marseille Université, 13385 Marseille Cedex 5, France.
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Brunel
authors.affiliation: Department of Cellular and Molecular Medicine, Ottawa, ON K1H8M5, Canada.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Béïque
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H8M5, Canada; University of Ottawa Heart Institute, Ottawa, ON K1Y4W7, Canada; Department of Medicine, University of Ottawa, Ottawa, ON K1H8M5, Canada.
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
authors.affiliation: Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Departments of Cell Biology and Anatomy & Psychiatry, University of Calgary, Calgary, AB T2N4N1, Canada.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Hill
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, ON K1H8M5, Canada; Department of Cellular and Molecular Medicine, Ottawa, ON K1H8M5, Canada; Department of Medicine, University of Ottawa, Ottawa, ON K1H8M5, Canada. Electronic address: hchen@uottawa.ca.
authors.forename: Hsiao-Huei
authors.initials: HH
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators; D003593:Cytoplasm / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D060588:LIM Domain Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013315:Stress, Psychological / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D060588:LIM Domain Proteins; C491976:Lmo4 protein, mouse; D043884:Receptor, Cannabinoid, CB1