A late phase of cerebellar long-term depression requires activation of CaMKIV and CREB.
Recently, it has been shown that cerebellar LTD has a late phase that may be blocked by protein synthesis inhibitors. To understand the mechanisms underlying the late phase, we interfered with the activation of transcription factors that might couple synaptic activation to protein synthesis. Particle-mediated transfection of cultured Purkinje neurons with an expression vector encoding a dominant inhibitory form of CREB resulted in a nearly complete blockade of the late phase. Kinases that activate CREB were inhibited, and LTD was assessed. Inhibition of PKA or the MAPK/RSK cascades were without effect on the late phase, while constructs designed to interfere with CaMKIV function attenuated the late phase. These results indicate that the activation of CaMKIV and CREB are necessary to establish a late phase of cerebellar LTD.
Ahn
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S
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Ginty
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DD
Linden
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D000818:Animals; D002118:Calcium / Q000032:analysis; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002227:Carbazoles; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes; D016257:Fura-2; D018698:Glutamic Acid / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009433:Neural Inhibition / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011689:Purkinje Cells / Q000737:chemistry / Q000166:cytology / Q000201:enzymology*; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics; D013873:Thionucleotides / Q000494:pharmacology; D014162:Transfection
D002227:Carbazoles; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D007211:Indoles; D011758:Pyrroles; D013873:Thionucleotides; D018698:Glutamic Acid; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; C057416:KT 5720; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517685:Camk4 protein, mouse; D002118:Calcium; D016257:Fura-2