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Retrograde cPLA2α/Arachidonic Acid/2-AG Signaling Is Essential for Cerebellar Depolarization-Induced Suppression of Excitation and Long-Term Potentiation

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Abstract

Cytosolic phospholipase A2 alpha (cPLA2α) responds to micromolar intracellular Ca2+ and produces arachidonic acid, which regulates cellular homeostasis, neurotoxicity, and inflammation. Endocannabinoids are the derivates of arachidonic acid and widely distributed in the cerebellum. However, the role of cPLA2α/arachidonic acid pathway in cerebellar synaptic transmission and plasticity is unknown. We utilized cPLA2α knockout mice and slice whole-cell patch clamp to study the action of cPLA2α/arachidonic acid signaling on the depolarization-induced suppression of excitation (DSE) and long-term potentiation at parallel fiber–Purkinje cell synapses. Our data showed that DSE was significantly inhibited but rescued by arachidonic acid in cPLA2α knockout mice. The degradation enzyme of 2-arachidonoylglycerol (2-AG), monoacylglycerol lipase, blocked DSE, while another catabolism enzyme for N-arachidonoylethanolamine, fatty acid amide hydrolase, did not, suggesting 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 is sufficient to inhibit cPLA2α/arachidonic acid-mediated DSE. On the other hand, we found that 1 Hz parallel fiber stimuli-triggered long-term potentiation (LTP) was deficient in cPLA2α knockout mice. LTP was also inhibited when AACOCF3, an inhibitor of cPLA2α, was given. Arachidonic acid was necessary for the LTP induction. Therefore, these data showed that cPLA2α/arachidonic acid/2-AG signaling pathway mediates DSE and LTP at parallel fiber–Purkinje cell synapse.

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Acknowledgments

We thank Dr. Adam Sapirstein (Johns Hopkins University, Baltimore, MD) for providing the cPLA2α knockout mice. We are grateful for helpful advice from members of Shen’s lab. This work was supported by the National Foundation of Natural Science of China (30600168, 31070945, 31100780 and 31200818) and the Foundation of Zhejiang Educational Committee, China (Y201121662 and Y20070109).

Conflict of interest

There are no conflicts of interest for Li-Da Su, De-Juan Wang, Dong Yang, Ying Shen, and Ying-Hong Hu.

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Authors and Affiliations

  1. Neuroscience Care Unit, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, People’s Republic of China

    Li-Da Su & Ying-Hong Hu

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

    De-Juan Wang, Dong Yang & Ying Shen

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  1. Li-Da Su
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  2. De-Juan Wang
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  3. Dong Yang
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  4. Ying Shen
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Correspondence to Ying Shen or Ying-Hong Hu.

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Li-Da Su and De-Juan Wang contributed equally to this work.

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Su, LD., Wang, DJ., Yang, D. et al. Retrograde cPLA2α/Arachidonic Acid/2-AG Signaling Is Essential for Cerebellar Depolarization-Induced Suppression of Excitation and Long-Term Potentiation. Cerebellum 12, 297–299 (2013). https://doi.org/10.1007/s12311-012-0444-9

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