Cannabinoids are part of an endogenous signaling system consisting of cannabinoid receptors and endogenous cannabinoids (eCBs) as well as the enzymatic machinery for their synthesis and degradation. Depolarization-induced suppression of excitation (DSE) is a form of cannabinoidCB₁ receptor-mediated inhibition of synaptic transmission that involves the production of the eCB 2-arachidonoyl glycerol (2-AG). Both DGLα and DGLβ can produce 2-AG in vitro but evidence from knockout animals argues strongly for a predominant, even exclusive, role for DGLα in regulation of 2-AG-mediated synaptic plasticity. What role, if any, might be played by DGLβ remains largely unknown. Cultured autaptic hippocampal neurons exhibit robust DSE. With the ability to rapidly modulate expression of DGLα and DGLβ in these neurons with shRNA they are well-suited for a comparative study of the roles of each isoform in mediating DSE. We find that RNAi knockdown of DGLα substantially reduces autaptic DSE, shifting the ‘depolarization response curve’ from an ED50 value of 1.7 sec to 3.0 sec. Surprisingly, DGLβ knockdown diminishes DSE as much or more (ED50 6.4 sec), suggesting that DGLβ is also responsible for a portion of 2-AG production in autaptic neurons. Similarly, the two DGLs 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 DGLβ in modulating neurotransmission.
PMID: 23748223 [PubMed – as supplied by publisher] http://www.ncbi.nlm.nih.gov/pubmed/23748223