| Long-term depression (LTD) and long-term potentiation (LTP) at cerebellar parallel fiber-Purkinje cell (PF-PC) synapses play critical roles in motor learning. PF-PC synapses undergo two forms of LTP, which are expressed either presynaptically or postsynaptically depending on stimulus frequency. Upon PF stimulation at4-8Hz, presynaptically expressed LTP is evoked via presynaptic cyclic adenosine monophosphate signaling. The1Hz stimulation at PF-PC synapses induces a postsynaptically expressed LTP that requires a postsynaptic Ca2+transient, phosphatases and nitric oxide (NO). However, the mechanism underlying lHz PF-LTP remains unclear because none of the known events is related to each other. Although lipid signaling is implicated in diverse biological functions, its importance in synaptic mechanisms has become increasingly evident. Here, we demonstrated that1Hz PF-LTP requires postsynaptic cytosolic phospholipase A2α (cPLA2a)/arachidonic acid (AA) signaling and presynaptic endocannabinoid receptors. Using patch-clamp recording in cerebellar slices, we found that1Hz PF-LTP was abolished in cPLA2a-knock-out mice. This deficit was effectively rescued by the conjunction of1Hz PF stimulation and the local application of AA.2-Arachidonoylglycerol (2-AG) and the retrograde activation of cannabinoid receptor1(CB1R) were also involved in1Hz LTP because it was blocked by the hydrolysis of2-AG or by inhibiting CBlRs. The amount of NO released was detected using an NO electrode in cultured granule cells and PF terminals. Our results showed that the activation of CBlRs at PF terminals activated NO synthetase and promoted NO production. The1Hz PF-stimuli evoked limited NO, but100Hz PF stimulation generated a large amount. Therefore, lHz PF-LTP, distinct from classical postsynaptically expressed plasticity, requires concurrent presynaptic and postsynaptic activity. In addition, NO of sufficient amplitude decides between the weakening and strengthening of PF-PC synapses. |
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