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TitleChronic stress induces anxiety via an amygdalar intracellular cascade that impairs endocannabinoid signaling.
Publication TypeJournal Article
Year of Publication2015
AuthorsQin, Zhaohong, Xun Zhou, Nihar R. Pandey, Haley A. Vecchiarelli, Chloe A. Stewart, Xia Zhang, Diane C. Lagace, Jean Michel Brunel, Jean-Claude Béïque, Alexandre F. R. Stewart, Matthew N. Hill, and Hsiao-Huei Chen
JournalNeuron
Volume85
Issue6
Pagination1319-31
Date Published2015 Mar 18
ISSN1097-4199
KeywordsAdaptor Proteins, Signal Transducing, Amygdala, Animals, Anxiety, Cannabinoid Receptor Modulators, Cytoplasm, Endocannabinoids, Intracellular Space, LIM Domain Proteins, Mice, Mice, Knockout, Mice, Transgenic, Receptor, Cannabinoid, CB1, Signal Transduction, Stress, Psychological
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.

DOI10.1016/j.neuron.2015.02.015
Alternate JournalNeuron
PubMed ID25754825
Grant List / / Canadian Institutes of Health Research / Canada