Genetic Disruption of 2-Arachidonoylglycerol Synthesis Reveals a Key Role for Endocannabinoid Signaling in Anxiety Modulation

Endocannabinoid (eCB) signaling has been heavily implicated in the modulation of anxiety and depressive behaviors and emotional learning. However, the role of the most-abundant endocannabinoid 2-arachidonoylglycerol (2-AG) in the physiological regulationof affective behaviors is not well understood. Here,we show that genetic deletion of the 2-AG syntheticenzyme diacylglycerol lipase α (DAGLα) inmice reduces brain, but not circulating, 2-AG levels.DAGLα deletion also results in anxiety-like and sex-specific anhedonic phenotypes associated withimpaired activity-dependent eCB retrograde signaling at amygdala glutamatergic synapses. Importantly, acute pharmacological normalization of 2-AG levels reverses both phenotypes of DAGLα-deficient mice. These data suggest 2-AG deficiency could contribute to the pathogenesis of affective disorders and that pharmacological normalization of 2-AG signaling could represent an approach for the treatment of mood and anxiety disorders. The role of the primary endogenous cannabinoid 2-AG in mood and anxiety regulation is not well understood. Shonesy etal. show that deletion of a primary 2-AG synthetic enzyme, DAGLα, results in anxiety and sex-specific depressive phenotypes, which can be rapidly reversed by pharmacological normalization of endocannabinoid levels.