Protein phosphatase 2A inhibition induces cerebellar long-term depression and declustering of synaptic AMPA receptor.
Phosphorylation of synaptic (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) (AMPA) receptors (AMPARs) is an essential component of cerebellar long-term depression (LTD), a form of synaptic plasticity involved in motor learning. Here, we report that protein phosphatase 2A (PP-2A) plays a specific role in controlling synaptic strength and clustering of AMPARs at synapses between granule cells and Purkinje cells. In 22- to 35-day cerebellar cultures, specific inhibition of postsynaptic PP-2A by fostriecin (100 nM) or cytostatin (10-60 microM) induced a gradual and use-dependent decrease of synaptic current evoked by the stimulation of a single granule cell, without altering receptor kinetics nor passive electrical properties. By contrast, PP-2A inhibition had no effect on immature Purkinje cells (12-15 days). Concurrent PP-2A inhibition and AMPAR stimulation induced a reduction of miniature synaptic currents and a reduction of AMPAR density at synapses. Either PP-2A inhibitor alone or AMPA stimulation alone had no significant effect. Inhibition of PP-1 by inhibitor 1 (10-27 units/microl) had no effect on synaptic current. Synaptic depression induced by PP-2A inhibition occluded subsequent induction of LTD by conjunctive stimulation and was abolished by a calcium chelator or a protein kinase inhibitor, suggesting a shared molecular pathway and involvement of PP-2A in LTD induction.
Launey
T
T
Laboratory for Memory and Learning, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. t_launey@brain.riken.go.jp
Endo
S
S
Sakai
R
R
Harano
J
J
Ito
M
M
D000818:Animals; D002531:Cerebellum / Q000201:enzymology* / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D054648:Protein Phosphatase 2; D018091:Receptors, AMPA / Q000378:metabolism*
D018091:Receptors, AMPA; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2