Jain_2013_Mol.Pharmacol_84_296

Cannabinoids are part of an endogenous signaling system consisting of cannabinoid receptors and endogenous cannabinoids as well as the enzymatic machinery for their synthesis and degradation. Depolarization-induced suppression of excitation (DSE) is a form of cannabinoid CB(1) receptor-mediated inhibition of synaptic transmission that involves the production of the endogenous cannabinoid 2-arachidonoyl glycerol (2-AG). Both diacylglycerol lipase alpha (DAGLalpha) and DAGLbeta can produce 2-AG in vitro, but evidence from knockout animals argues strongly for a predominant, even exclusive, role for DAGLalpha in regulation of 2-AG-mediated synaptic plasticity. What role, if any, might be played by DAGLbeta remains largely unknown. Cultured autaptic hippocampal neurons exhibit robust DSE. With the ability to rapidly modulate expression of DAGLalpha and DAGLbeta in these neurons with short hairpin RNA, they are well suited for a comparative study of the roles of each isoform in mediating DSE. We find that RNA interference knockdown of DAGLalpha substantially reduces autaptic DSE, shifting the "depolarization-response curve" from an ED(50) value of 1.7 seconds to 3.0 seconds. Surprisingly, DAGLbeta knockdown diminishes DSE as much or more (ED(50) 6.4 seconds), suggesting that DAGLbeta is also responsible for a portion of 2-AG production in autaptic neurons. Similarly, the two DAGLs both contribute to the production of 2-AG via group I metabotropic glutamate receptors. Our results provide the first explicit evidence for a role of DAGLbeta in modulating neurotransmission.