Neurensin-2 is a negative regulator of CB1 receptor.

Major depressive disorder (MDD) is a leading cause of disability worldwide. Unfortunately, approximately 30 % of MDD patients do not respond to available antidepressants, and characterization of novel molecular mediators of MDD is urgently needed. Chronic stress, a key risk factor for MDD, induces widespread neurobiological changes, including alterations in synaptic plasticity and neurotransmission. However, the molecular mechanisms mediating these effects remain poorly defined. In this study, we provide evidence that Neurensin-2, a stress-inducible vesicular protein, regulates the cannabinoid receptor 1 (CB1R), an important mediator of depression. In N2a cells, overexpression of Neurensin-2 was associated with reduced CB1R expression and attenuation of its downstream signaling; the Akt, mTOR, and Erk1/2 pathways. In these cells, Neurensin-2 co-localized with CB1R and reduced the expression of this receptor in both the membrane and intracellular organelles. The Neurensin-2-CB1R relationship was examined in vivo using the chronic social defeat stress (CSDS) model, where stress exposure was accompanied by increased Nrsn2 and decreased Cnr1 expression in the mouse hippocampus. Notably, stress-induced Cnr1 downregulation was not observed in Neurensin-2 knockout mice, suggesting that Neurensin-2 plays a role in stress-induced downregulation of CB1R in vivo. We further confirmed these expression patterns within the hippocampal inhibitory neuronal population that highly co-expresses Neurensin-2 and CB1R, the CCK-positive hippocampal interneurons. These findings uncover a novel stress-induced pathway that inhibits CB1R signaling by Neurensin-2. Thus, we suggest that Neurensin-2 is a potential therapeutic target for treatment-resistant depression.