A transcription factor-binding domain of the coactivator CBP is essential for long-term memory and the expression of specific target genes.
Transcriptional activation is a key process required for long-term memory formation. Recently, the transcriptional coactivator CREB-binding protein (CBP) was shown to be critical for hippocampus-dependent long-term memory and hippocampal synaptic plasticity. As a coactivator with intrinsic histone acetyltransferase activity, CBP interacts with numerous transcription factors and contains multiple functional domains. Currently, it is not known which transcription factor-binding domain of CBP is essential for memory storage. Using mice that carry inactivating mutations in the CREB-binding (KIX) domain of the coactivator CBP (CBPKIX/KIX mice), we show that the KIX domain is required for long-term memory storage. These results are the first to identify an in vivo function for the KIX domain of CBP in the brain, and they suggest that KIX-interacting transcription factors recruit CBP histone acetyltransferase activity during long-term memory storage. One such KIX-interacting factor is the transcription factor CREB. Using quantitative real-time RT-PCR, we find that the expression of specific CREB target genes is reduced in the hippocampi of CBPKIX/KIX mice during memory consolidation. The recruitment of the transcriptional coactivator CBP via the KIX domain thus imparts target gene-dependent selectivity to CREB-driven transcriptional regulation, thereby activating genes required for the long-term storage of hippocampus-dependent memory.
Wood
Marcelo A
MA
Department of Neurobiology & Behavior, Center for the Neurobiology of Learning & Memory, University of California at Irvine 92697, and Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. mwood@uci.edu
Attner
Michelle A
MA
Oliveira
Ana M M
AM
Brindle
Paul K
PK
Abel
Ted
T
D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism; D008024:Ligands; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*
D008024:Ligands; D014157:Transcription Factors; D050882:CREB-Binding Protein