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

Abstract

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 cPLA 2 α knockout blocked LTD induction, which was rescued by replenishing arachidonic acid (AA) or prostaglandin (PG) D 2 or E 2 . Moreover, cyclooxygenase (COX)-2 inhibitors block LTD, which is rescued by supplementing PGD 2 /E 2 . The blockade or rescue occurs when these reagents are applied within a time window of 5-15 min following the onset of LTD-inducing stimulation. Furthermore, PGD 2 /E 2 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 PGD 2 /E 2 mediates LTD jointly with PKC, and suggest possible pathways for their interaction. Finally, we demonstrate in awake mice that cPLA 2 α deficiency or COX-2 inhibition attenuates short-term adaptation of optokinetic eye movements, supporting the view that LTD underlies motor learning.

Reassessment of long-term depression in cerebellar Purkinje cells in mice carrying mutated GluA2 C terminus

“…In a previous control study using a K + -based internal solution, the Cj dependence of LTD induction was confirmed by the absence of LTD after the separate application of depolarizing pulses (20). In this study, we applied 50-ms depolarizing pulses at 1 Hz for 3 min separately from PF stimuli.…”

“…It has been shown that there is a second Cj-LTD pathway involving cytosolic phospholipase A 2 α, cyclooxygenase-2, and prostaglandin D2/E2 (20). This pathway might also mediate LTD induction under stronger Cj.…”

“…3A) (19,20). The patch pipette was filled with a Cs + -based internal solution to improve space clamping along PC dendrites by blocking K + channels (15,21).…”

“…This protocol was originally used by Steinberg et al (15), with five PF stimulations at 100 Hz concomitant with somatic depolarization (100-ms duration) applied at 2-s intervals for 1 min. This protocol induced LTD in slices obtained from young mice [postnatal day (P) [20][21][22][23][24][25] in WT, but in neither K882A nor Δ7 PCs (15). In the present study, however, when applied to mature WT mice (3-6 mo), the original protocol of Steinberg et al (15) was ineffective for inducing LTD (98.0 ± 5.7%, n = 4, P = 0.78, paired t test).…”

Functional and Physical Interaction of Diacylglycerol Kinase ζ with Protein Kinase Cα Is Required for Cerebellar Long-Term Depression

“…A previous study proposed a model of the reciprocal regulation of DGK by PKC␣ (Luo et al, 2003b): activated PKC␣ phosphorylates DGK, the phosphorylation of DGK results in the dissociation of PKC␣ from DGK, and the dissociation allows PKC␣ to remain active without being suppressed by DGK. Because PKC␣ activation is critical for LTD, it is possible that such reciprocal regulation occurs during LTD. We tested this possibility by two experiments.…”