Retrograde cPLA2α/arachidonic acid/2-AG signaling is essential for cerebellar depolarization-induced suppression of excitation and long-term potentiation.

Cytosolic phospholipase A2 alpha (cPLA2α) responds to micromolar intracellular Ca(2+) 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 Ca(2+)-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.