Cytosolic phospholipase A2 alpha/arachidonic acid signaling mediates depolarization-induced suppression of excitation in the cerebellum

De-Juan Wang; Dong Yang; Li-Da Su; Ya-jun Xie; Lin Zhou; Cheng-Long Sun; Yin Wang; Xin-Xin Wang; Liang Zhou; Ying Shen

doi:10.1371/journal.pone.0041499

Cytosolic phospholipase A2 alpha/arachidonic acid signaling mediates depolarization-induced suppression of excitation in the cerebellum

PLoS One. 2012;7(8):e41499. doi: 10.1371/journal.pone.0041499. Epub 2012 Aug 22.

Authors

De-Juan Wang¹, Dong Yang, Li-Da Su, Ya-jun Xie, Lin Zhou, Cheng-Long Sun, Yin Wang, Xin-Xin Wang, Liang Zhou, Ying Shen

Affiliation

¹ Key Laboratory of Medical Neurobiology of the Ministry of Health, Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.

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(2)α) knock-out mice and whole-cell patch clamp in cerebellar slices to observed the action of cPLA(2)α/arachidonic acid signaling on DSE at parallel fiber-Purkinje cell synapse. Our data showed that DSE was significantly inhibited in cPLA(2)α 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(2)α/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(2)α/arachidonic acid/2-AG signaling pathway mediates DSE at parallel fiber-Purkinje cell synapse.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arachidonic Acid / metabolism*
Arachidonic Acids / metabolism
Calcium / metabolism
Electrophysiological Phenomena* / drug effects
Endocannabinoids / metabolism
Gene Knockout Techniques
Glycerides / metabolism
Group IV Phospholipases A2 / deficiency
Group IV Phospholipases A2 / genetics
Group IV Phospholipases A2 / metabolism*
Indoles / pharmacology
Mice
Potassium / pharmacology
Potassium Channel Blockers / pharmacology
Purkinje Cells / cytology*
Purkinje Cells / drug effects
Purkinje Cells / metabolism
Purkinje Cells / physiology*
Signal Transduction* / drug effects
Synapses / drug effects
Synapses / metabolism
Synapses / physiology

Substances

Arachidonic Acids
Endocannabinoids
Glycerides
Indoles
Potassium Channel Blockers
Arachidonic Acid
paxilline
glyceryl 2-arachidonate
Group IV Phospholipases A2
Potassium
Calcium

Grants and funding

This work was supported by grants from the National Basic Research Program (973) of the Ministry of Science and Technology of China (2009CB94140 and 2011CB5044000), the National Foundation of Natural Science of China (30600168, 31070945 and 31100780), a joint grant from the National Foundation of Natural Science and the Research Grants Council of Hong Kong, China (30731160616), a New Century Talent Award of the Ministry of Education of China (NCET-07-0751) and the Zhejiang Provincial Foundation of Natural Science of China (R206018). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.