TY - JOUR T1 - Diacylglycerol Lipase<em>α</em> (DAGL<em>α</em>) and DAGL<em>β</em> Cooperatively Regulate the Production of 2-Arachidonoyl Glycerol in Autaptic Hippocampal Neurons JF - Molecular Pharmacology JO - Mol Pharmacol SP - 296 LP - 302 DO - 10.1124/mol.113.085217 VL - 84 IS - 2 AU - Tarun Jain AU - Jim Wager-Miller AU - Ken Mackie AU - Alex Straiker Y1 - 2013/08/01 UR - http://molpharm.aspetjournals.org/content/84/2/296.abstract N2 - 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 CB1 receptor–mediated inhibition of synaptic transmission that involves the production of the endogenous cannabinoid 2-arachidonoyl glycerol (2-AG). Both diacylglycerol lipase α (DAGLα) and DAGLβ can produce 2-AG in vitro, but evidence from knockout animals argues strongly for a predominant, even exclusive, role for DAGLα in regulation of 2-AG–mediated synaptic plasticity. What role, if any, might be played by DAGLβ remains largely unknown. Cultured autaptic hippocampal neurons exhibit robust DSE. With the ability to rapidly modulate expression of DAGLα and DAGLβ 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 DAGLα substantially reduces autaptic DSE, shifting the “depolarization-response curve” from an ED50 value of 1.7 seconds to 3.0 seconds. Surprisingly, DAGLβ knockdown diminishes DSE as much or more (ED50 6.4 seconds), suggesting that DAGLβ 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 DAGLβ in modulating neurotransmission. ER -