Lipid signaling in cytosolic phospholipase A2alpha-cyclooxygenase-2 cascade mediates cerebellar long-term depression and motor learning.
In this study, we show the crucial roles of lipid signaling in long-term depression (LTD), that is, synaptic plasticity prevailing in cerebellar Purkinje cells. In mouse brain slices, we found that cPLA(2)alpha 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)alpha deficiency or COX-2 inhibition attenuates short-term adaptation of optokinetic eye movements, supporting the view that LTD underlies motor learning.
Ito Laboratory and Nagao Laboratory, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
Tung Dinh
TD
Le
Yoshinori
Y
Shirai
Takehito
T
Okamoto
Tetsuya
T
Tatsukawa
Soichi
S
Nagao
Takao
T
Shimizu
Masao
M
Ito
D000814:Aniline Compounds; D000818:Animals; D002531:Cerebellum / Q000378:metabolism / Q000502:physiology*; D002934:Cinnamates; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005452:Fluoresceins; D054513:Group IV Phospholipases A2 / Q000378:metabolism*; D007858:Learning / Q000502:physiology*; D050356:Lipid Metabolism / Q000502:physiology*; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000502:physiology*; D009281:Naphthalenes; D010654:Phenylbutyrates; D015398:Signal Transduction / Q000502:physiology*
C487890:4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid; D000814:Aniline Compounds; D002934:Cinnamates; D005452:Fluoresceins; D009281:Naphthalenes; C411295:ONO 8713; C503942:Oregon green 488 BAPTA-1; D010654:Phenylbutyrates; D051546:Cyclooxygenase 2; D054513:Group IV Phospholipases A2