SRF binding to SRE 6.9 in the Arc promoter is essential for LTD in cultured Purkinje cells

• DOI: 10.1038/nn.2611
• Publication Date: 2010-08-08T18:09:53Z
• Authors: Constance Smith-H...; Bo Xiao; Rongkang Deng; Yifei Ji; Xia Zhao; Jason D Shepherd; Guido Posern; Dietmar Kuhl; Richard L Huganir; David D Ginty; Paul F Worley; David J Linden
• Keywords: Mice, Knockout; Serum Response Factor; 0303 health sciences; Time Factors; Long-Term Synaptic Depression; Mice, Transgenic; Nerve Tissue Proteins; Transfection; Cytoskeletal Proteins; Mice; Purkinje Cells; 03 medical and health sciences; Mutation; Trans-Activators; Animals; Promoter Regions, Genetic; Cells, Cultured

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.