2. Academic Validation
  3. Chronic stress induces anxiety via an amygdalar intracellular cascade that impairs endocannabinoid signaling

Chronic stress induces anxiety via an amygdalar intracellular cascade that impairs endocannabinoid signaling

  • Neuron. 2015 Mar 18;85(6):1319-31. doi: 10.1016/j.neuron.2015.02.015.
Zhaohong Qin 1,  Xun Zhou 1,  Nihar R Pandey 1,  Haley A Vecchiarelli 2,  Chloe A Stewart 1,  Xia Zhang 3,  Diane C Lagace 4,  Jean Michel Brunel 5,  Jean-Claude Béïque 4,  Alexandre F R Stewart 6,  Matthew N Hill 2,  Hsiao-Huei Chen 7
Affiliations

Affiliations

  • 1 Ottawa Hospital Research Institute, Ottawa, ON K1H8M5, Canada.
  • 2 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.
  • 3 Royal Ottawa Mental Health Centre, Ottawa, ON K1Z7K4, Canada; Department of Cellular and Molecular Medicine, Ottawa, ON K1H8M5, Canada.
  • 4 Department of Cellular and Molecular Medicine, Ottawa, ON K1H8M5, Canada.
  • 5 Centre de Recherche en Cancérologie de Marseille, Laboratory of Integrative Structural & Chemical Biology (iSCB), Aix-Marseille Université, 13385 Marseille Cedex 5, France.
  • 6 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.
  • 7 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: [email protected].
PMID: 25754825 DOI: 10.1016/j.neuron.2015.02.015
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.

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