Cytosolic phospholipase A 2 alpha/arachidonic acid signaling mediates depolarization-induced suppression of excitation in the cerebellum

Abstract

Background: Depolarization-induced suppression of excitation (DSE) at parallel fiber-Purkinje cell synapse is an endocannabinoid-mediated short-term retrograde plasticity. Intracellular Ca 2+ elevation is critical for the endocannabinoid production and DSE. Nevertheless, how elevated Ca 2+ leads to DSE is unclear. Methodology/Principal Findings: We utilized cytosolic phospholipase A 2 alpha (cPLA 2α) knock-out mice and whole-cell patch clamp in cerebellar slices to observed the action of cPLA 2α/arachidonic acid signaling on DSE at parallel fiber-Purkinje cell synapse. Our data showed that DSE was significantly inhibited in cPLA 2α knock-out mice, which was rescued by arachidonic acid. The degradation enzyme of 2-arachidonoylglycerol (2-AG), monoacylglycerol lipase (MAGL), blocked DSE, while another catabolism enzyme for N-arachidonoylethanolamine (AEA), fatty acid amide hydrolase (FAAH), did not affect DSE. These results suggested that 2-AG is responsible for DSE in Purkinje cells. Co-application of paxilline reversed the blockade of DSE by internal K +, indicating that large conductance Ca 2+-activated potassium channel (BK) is sufficient to inhibit cPLA 2α/arachidonic acid-mediated DSE. In addition, we showed that the release of 2-AG was independent of soluble NSF attachment protein receptor (SNARE), protein kinase C and protein kinase A. Conclusions/Significance: Our data first showed that cPLA 2α/arachidonic acid/2-AG signaling pathway mediates DSE at parallel fiber-Purkinje cell synapse. © 2012 Wang et al.