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A transcription factor-binding domain of the coactivator CBP is essential for long-term memory and the expression of
Marcelo A Wood1, Michelle A Attner, Ana M M Oliveira
1Department 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
Abstract:
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.
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