Augmentation of 2-arachidonoylglycerol signaling in astrocytes maintains synaptic functionality by regulation of...

2-Arachidonoylglycerol (2-AG), the most abundant endocannabinoid, displays anti-inflammatory and neuroprotective properties. Inhibition of 2-AG degradation by inactivation of monoacylglycerol lipase (MAGL), a key enzyme degrading 2-AG in the brain, alleviates neuropathology and improves synaptic and cognitive functions in animal models of neurodegenerative diseases. In particular, global inactivation of MAGL by genetic deletion of mgll enhances hippocampal long-term potentiation (LTP) and hippocampus-dependent learning and memory. However, our understanding of the molecular mechanisms by which chronic inactivation of MAGL enhances synaptic activity is still limited. Here, we provide evidence that pharmacological inactivation of MAGL suppresses hippocampal expression of miR-30b, a small non-coding microRNA, and upregulates expression of its targets, including ephrin type-B receptor 2 (ephB2), sirtuin1 (sirt1), and glutamate ionotropic receptor AMPA type subunit 2 (GluA2). Importantly, suppression of miR-30b and increase of its targets by inactivation of MAGL result primarily from inhibition of 2-AG metabolism in astrocytes, rather than in neurons. Inactivation of MAGL in astrocytes prevents miR-30b overexpression-induced impairments in synaptic transmission and long-term potentiation (LTP) in the hippocampus. Suppression of miR-30b expression by inactivation of MAGL is apparently associated with augmentation of 2-AG signaling, as 2-AG induces a dose-dependent decrease in expression of miR-30b. 2-AG- or MAGL inactivation-suppressed expression of miR-30b is not mediated via CB1R, but by peroxisome proliferator-activated receptor γ (PPARγ). This is further supported by the results showing that MAGL inactivation-induced downregulation of miR-30b and upregulation of its targets are attenuated by antagonism of PPARγ, but mimicked by PPARγ agonists. In addition, we observed that 2-AG-induced reduction of miR-30b expression is mediated via NF-kB signaling. Our study provides evidence that 2-AG signaling in astrocytes plays an important role in maintaining the functional integrity of synapses in the hippocampus by regulation of miR-30b expression.