Lipid signaling in cytosolic phospholipase A2α– cyclooxygenase-2 cascade mediates cerebellar long- term depression and motor learning.

In this study, we show the crucial roles of lipid signaling in longterm depression (LTD), that is, synaptic plasticity prevailing in cerebellar Purkinje cells. In mouse brain slices,, we found that cPLA2a knockout blocked LTD induction, which was rescued by replenishing arachidonic acid (AA) or prostaglandin (PG) D2 or E2. Moreover, cyclooxygenase (COX)-2 inhibitors block LTD, which is rescued by supplementing PGD2/E2. The blockade or rescue occurs when these reagents are applied within a time window of 5-15 mm following the onset of LTD-inducing stimulation. Furthermore, PGD2/E2 facilitates the chemical induction of LTD by a PKC activator but is unable to rescue the LTD blocked by a PKC inhibitor. We conclude that PGD2/E2 mediates LTD jointly with PKC, and suggest possible pathways for their interaction. Finally, we demonstrate in awake mice that cPLA2α deficiency or COX-2 inhibition attenuates short-term adaptation of optokinetic eye movements, supporting the view that LTD underlies motor learning. [ABSTRACT FROM AUTHOR]