Cytosolic Phospholipase A2 alpha/Arachidonic Acid Signaling Mediates Depolarization-Induced Suppression of Excitation in the Cerebellum

De-Juan Wang,Cheng-Long Sun,Ying Shen,Yin Wang,Lin Zhou,Liang Zhou,Ya-Jun Xie,Li-Da Su,Xin-Xin Wang,Dong Yang,Huaibin Cai

doi:10.1371/journal.pone.0041499

Abstract

BackgroundDepolarization-induced suppression of excitation (DSE) at parallel fiber-Purkinje cell synapse is an endocannabinoid-mediated short-term retrograde plasticity. Intracellular Ca2+ elevation is critical for the endocannabinoid production and DSE. Nevertheless, how elevated Ca2+ leads to DSE is unclear.Methodology/Principal FindingsWe utilized cytosolic phospholipase A2 alpha (cPLA2α) knock-out mice and whole-cell patch clamp in cerebellar slices to observed the action of cPLA2α/arachidonic acid signaling on DSE at parallel fiber-Purkinje cell synapse. Our data showed that DSE was significantly inhibited in cPLA2α 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 Ca2+-activated potassium channel (BK) is sufficient to inhibit cPLA2α/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/SignificanceOur data first showed that cPLA2α/arachidonic acid/2-AG signaling pathway mediates DSE at parallel fiber-Purkinje cell synapse.

Highlights

Depolarization-induced suppression of excitation (DSE) was first reported at excitatory synapse in cerebellar Purkinje cells [1]
Protein kinase A (PKA) we showed that cytosolic phospholipase A2 alpha (cPLA2a)/arachidonic acid signaling was essential for DSE induction, several important questions in Purkinje cell DSE remain to be elucidated
The main finding of the present study is that DSE at parallel fiber-Purkinje cell synapse was mediated by the cPLA2a/ arachidonic acid pathway

Summary

Introduction

Depolarization-induced suppression of excitation (DSE) was first reported at excitatory synapse in cerebellar Purkinje cells [1]. While DSE is a short-term retrograde plasticity associated with a change in paired-pulse ratio [1,2,3], it is initiated by the postsynaptic depolarization that activates local dendritic Ca2+ spikes [1,4]. Both blocking dendritic Ca2+ spikes by hyperpolarization and intracellular injection of 1,2-bis(o-aminophenoxy)ethane-N,N,N9,N9-tetraacetic acid (BAPTA) prevent DSE [1,4], indicating that the Ca2+ elevation is critical for the DSE induction. Depolarization-induced suppression of excitation (DSE) at parallel fiber-Purkinje cell synapse is an endocannabinoid-mediated short-term retrograde plasticity.

Methods

Results

Conclusion