Diacylglycerol Lipasea (DAGLa) and DAGLb Cooperatively Regulate the Production of 2-Arachidonoyl Glycerol in Autaptic Hippocampal Neurons

Cannabinoids are part of an endogenous signaling system consisting of cannabinoid receptors and endogenous cannabi-noids as well as the enzymatic machinery for their synthesis and degradation. Depolarization-induced suppression of excitation (DSE) is a form of cannabinoid CB1 receptor–mediated inhibition of synaptic transmission that involves the production of the endogenous cannabinoid 2-arachidonoyl glycerol (2-AG). Both diacylglycerol lipase a (DAGLa) and DAGLb can produce 2-AG in vitro, but evidence from knockout animals argues strongly for a predominant, even exclusive, role for DAGLa in regulation of 2-AG–mediated synaptic plasticity. What role, if any, might be played by DAGLb remains largely unknown. Cultured autaptic hippocampal neurons exhibit robust DSE. With the ability to rapidly modulate expression of DAGLa and DAGLb 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 DAGLa substantially reduces autaptic DSE, shifting the “depolarization-response curve ” from an ED50 value of 1.7 seconds to 3.0 seconds. Surprisingly, DAGLb knockdown diminishes DSE as much or more (ED50 6.4 seconds), suggesting that DAGLb is also responsible for a portion of 2-AG production in autaptic neurons. Similarly, the two DAGLs both contribute to the pro-duction of 2-AG via group I metabotropic glutamate receptors. Our results provide the first explicit evidence for a role of DAGLb in modulating neurotransmission