Editors' ChoiceNeuroscience

How stress causes anxiety

Sci. Signal.  24 Mar 2015:
Vol. 8, Issue 369, pp. ec68
DOI: 10.1126/scisignal.aab1612

Chronic stress can lead to psychosocial disorders such as anxiety. The anxiolytic effects of cannabis are mediated by cannabinoid (CB) receptors in the brain. The production of endogenous CB receptor ligands (collectively called endocannabinoids) is promoted by metabotropic glutamate receptors (mGluRs), which are G protein–coupled receptors that can signal through G proteins or following phosphorylation through arrestins. Qin et al. identified a mechanism by which stress triggered anxiety by impairing endocannabinoid signaling in the brain. Mice that lacked LMO4 (LIM domain only 4), an inhibitor of the protein phosphatase PTP1B, in glutamatergic neurons exhibited anxiety-associated behaviors and decreased electrophysiological measures of endocannabinoid signaling in the amygdala. In these mice, the CB receptor was functionally intact, but the abundance of 2-arachidonoylglycerol (2-AG) was reduced and mGluR5 signaling measured by synaptic activity was impaired. Lysates from LMO4-deficient amygdala tissue had increased PTP1B activity, whereas the phosphorylation of mGluR5 was decreased. Knocking down LMO4 or expressing PTP1B decreased the abundance of phosphorylated mGluR5 in cultured F11 neuronal cells, and both wild-type and a substrate-trapping mutant of PTP1B bound mGluR5 in cell lysates. Application of trodusquemine, a small-molecule inhibitor of PTP1B, restored the phosphorylation of mGluR5 in F11 cells. Intraperitoneal injection of trodusquemine in LMO4-deficient mice increased the content of 2-AG in the amygdala, and either intra-amygdalar injection of trodusquemine or knocking down PTP1B in the amygdala alleviated anxiety in mice as measured by behavioral tests. Repeatedly subjecting wild-type mice to restraint stress increased the concentration of the stress hormone corticosterone in the serum and increased the proportion of active PTP1B and decreased endocannabinoid content in the amygdala. Chronically stressed mice had decreased palmitoylation of LMO4, which is necessary for inhibition of PTP1B, in the amygdala. Treating mice with trodusquemine or a glucocorticoid receptor antagonist prevented the stress-induced decrease in endocannabinoid content and the increase in PTP1B activity, respectively, and either treatment alleviated anxiety-associated behavior. The findings explain both how chronic stress can lead to anxiety and the anxiolytic effects of cannabis and provide additional targets for treating anxiety.

Z. Qin, X. Zhou, N. R. Pandey, H. A. Vecchiarelli, C. A. Stewart, X. Zhang, D. C. Lagace, J. M. Brunel, J. -C. Béïque, A. F. R. Stewart, M. N. Hill, H. -H. Chen, Chronic stress induces anxiety via an amygdalar intracellular cascade that impairs endocannabinoid signaling. Neuron 85, 1319–1331 (2015). [PubMed]