SRF binding to SRE 6.9 in the Arc promoter is essential for LTD in cultured Purkinje cells.
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.
Smith-Hicks
Constance
C
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Xiao
Bo
B
Deng
Rongkang
R
Ji
Yifei
Y
Zhao
Xia
X
Shepherd
Jason D
JD
Posern
Guido
G
Kuhl
Dietmar
D
Huganir
Richard L
RL
Ginty
David D
DD
Worley
Paul F
PF
Linden
David J
DJ
D000818:Animals; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D036881:Long-Term Synaptic Depression / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011689:Purkinje Cells / Q000502:physiology*; D026362:Serum Response Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection
D003598:Cytoskeletal Proteins; C511173:Mrtfa protein, mouse; D009419:Nerve Tissue Proteins; D026362:Serum Response Factor; D015534:Trans-Activators; C092069:activity regulated cytoskeletal-associated protein