Abstract
It has been suggested that gene expression and protein synthesis are required for both long-term memory consolidation and late phases of long-term potentiation and long-term depression (LTD). The necessary genes and the specific transcription factor binding sites in their promoters remain unknown. We found that inhibition of the transcription factor SRF or its cofactor MAL blocked the late phase of LTD in mouse cultured cerebellar Purkinje cells, as did deletion of the immediate early gene Arc. Using neuronal bacterial artificial chromosome (BAC) transfection, we found that, in Arc−/− cells transfected with a wild-type Arc BAC, late-phase LTD was rescued. However, mutation of one SRF-binding site in the Arc promoter (SRE 6.9) blocked this rescue. Co-transfection of wild-type Arc and SRF engineered to bind mutated SRE 6.9 restored late-phase LTD in Arc−/−, SRE 6.9 mutant BAC cells. Thus, SRF binding to SRE 6.9 in the Arc promoter is required for the late phase of cerebellar LTD.
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Acknowledgements
We thank D. VanNess for excellent technical assistance and to members of the Linden and Worley laboratories for helpful suggestions. M. Greenberg's laboratory (Harvard University) provided the Gal4-SRF fusion construct plasmid. The authors thank B. Knöll (University of Tübingen) for sharing β-actin constructs and for helpful suggestions. The FLAG-tagged dominant-negative MAL was a generous gift from R. Prywes (Columbia University). This work supported by grants from the US Public Health Service (NIH R37 MH51106 to D.J.L., P50 MH084020 to D.J.L., D.D.G., P.F.W. and R.L.H., and NIH 5K12 NS001696-07 to C.S.-H.), the National Basic Research Program of China (2004CB518800 to B.X. and 2004CB518800 to X.Z.) and the Science Fund for Creative Research Group, China (B.X.).
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C.S.-H. performed the immunohistochemistry and designed a portion of the study. B.X., R.D., Y.J. and X.Z. engineered the BACs. J.D.S. performed immunohistochemistry and wrote an early draft of the manuscript. G.P. provided mutant actin reagents and helped to design the experiments that used them. D.K. provided Arc−/− mice. R.L.H., D.D.G. and P.F.W. supervised the project. D.J.L. provided overall supervision of the project and conducted the electrophysiological and imaging experiments.
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Smith-Hicks, C., Xiao, B., Deng, R. et al. SRF binding to SRE 6.9 in the Arc promoter is essential for LTD in cultured Purkinje cells. Nat Neurosci 13, 1082–1089 (2010). https://doi.org/10.1038/nn.2611
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DOI: https://doi.org/10.1038/nn.2611
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