Anisomycin activates p38 MAP kinase to induce LTD in mouse primary visual cortex.
Anisomycin is both a well-established protein synthesis inhibitor and a potent activator of the p38/JNK MAPK pathway. It has been used to block the late phase of long-term potentiation (LTP) and long-term depression (LTD) in hippocampus. In this study, we have found that anisomycin produces a time-dependent decline in the magnitude of the field EPSP (fEPSP) in acute brain slices of mouse primary visual cortex. This anisomycin-mediated fEPSP depression occludes NMDA receptor-dependent LTD induced by low-frequency stimulation (LFS). In contrast, two other protein synthesis inhibitors, emetine and cycloheximide, have no effect either on baseline synaptic transmission or on LTD. Moreover, the decline of the fEPSP caused by anisomycin can be rescued by the application of the p38 inhibitor SB203580 but not by the JNK inhibitor SP600125. These results indicate that activation of p38 MAPK by anisomycin induces LTD and subsequently occludes electrically induced LTD. Also, the occlusion of LFS-LTD by anisomycin suggests that common mechanisms may be shared between the two forms of synaptic depression. Consistent with this view, bath application of a membrane permeant peptide derived from the carboxyl tail of GluR2 subunit of AMPA receptor, which specifically blocks regulated AMPA receptor endocytosis, thereby preventing the expression of LFS-induced LTD, significantly reduced the anisomycin-induced decline of the fEPSP. In conclusion, our results indicate that anisomycin produces long-lasting depression of AMPA receptor-mediated synaptic transmission by activating p38 MAPK-mediated endocytosis of APMA receptors in mouse primary visual cortex.
Xiong
Wei
W
Brain Research Center, University of British Columbia, 2211 Wesbrook Mall, Brain Research Center, Vancouver, Canada BC V6T 2B5. weixiong@interchange.ubc.ca
Kojic
Ljubomir Z
LZ
Zhang
Lanjing
L
Prasad
Shiv S
SS
Douglas
Robert
R
Wang
Yutian
Y
Cynader
Max S
MS
D000818:Animals; D000831:Animals, Newborn; D000841:Anisomycin / Q000494:pharmacology*; D015153:Blotting, Western / Q000379:methods; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects; D014793:Visual Cortex / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D000841:Anisomycin; D048051:p38 Mitogen-Activated Protein Kinases