2 Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan
3 Department of Anatomy and Embryology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
4 Section of Viral Vector Development, National Institute for Physiological Sciences, Okazaki 444-8585, Japan
SUMMARY
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 kainateinduced seizures in mice lacking the 2-AG synthesizing enzyme, diacylglycerol lipase a, 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 epileptogenesis and spontaneous seizures after kainateinduced status epilepticus. These results highlight critical roles of 2-AG signaling in the suppression of epileptic seizures.
Sugaya et al., 2016, Cell Reports 16, 1–11 August 2, 2016 a 2016 The Author(s).
