Crucial Roles of the Endocannabinoid 2-Arachidonoylglycerol in the Suppression of Epileptic Seizures

Endocannabinoid signaling is considered to suppress excessive excitability of neural circuits and to protect the brain from seizures. However, the precise mechanisms of this effect are poorly understood. Here, we report that 2-arachidonoylglycerol (2-AG), one of the two major endocannabinoids, is crucial for suppressing seizures. We found that kainate-induced seizures in mice lacking the 2-AG synthesizing enzyme, diacylglycerol lipase alpha, were much more severe compared with those in cannabinoid CB1 receptor knockout mice and were comparable to those in mice lacking both CB1- and CB2-receptor-mediated signaling. In the dentate gyrus, 2-AG suppressed excitatory input around the inner and middle molecular layers through CB1 and presumably CB2 receptors, respectively. This 2-AG-mediated suppression contributed to decreased granule cell excitability and the dampening of seizures. Furthermore, lack of 2-AG signaling enhanced kindling epilepto-genesis and spontaneous seizures after kainate-induced status epilepticus. These results highlight critical roles of 2-AG signaling in the suppression of epileptic seizures.