Chronic Stress Induces Anxiety via an Amygdalar Intracellular Cascade that Impairs Endocannabinoid Signaling

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. [Display omitted] •Mice with ablation of an endogenous PTP1B inhibitor LMO4 have anxiety•PTP1B dephosphorylates mGluR5 and impairs mGluR5-mediated eCB production•Glucocorticoids impair LMO4 palmitoylation and increase PTP1B activity•PTP1B inhibition in the amygdala restores eCBs and relieves stress-induced anxiety Collapse of endocannabinoid signaling in the amygdala underlies stress-induced anxiety. Qin et al. present a mechanism whereby stress (glucocorticoid) causes loss of LMO4-dependent inhibition of tyrosine phosphatase PTP1B that impairs mGluR5-mediated endocannabinoid production. Suppressing amygdalar PTP1B rescues stress-induced anxiety.