Figure 6.
HDAC inhibition enhances memory and synaptic plasticity via a CREB:CBP interaction. A, Decreases in CBP activity and histone acetylation impair long-term memory and long-lasting forms of LTP. Conversely, increasing histone acetylation enhances long-term memory and LTP (as shown in this study; for other references, see Discussion). Our results demonstrate that these enhancements occur via a CREB:CBP complex and transcription of particular CREB-regulated genes such as Nr4a1 and Nr4a2. B, A schematic diagram of how activation of CREB by phosphorylation in wild-type mice recruits CBP via the CREB-binding domain (KIX; shown as yellow crescent). CBP in turn becomes activated (possibly by phosphorylation via CaMKIV) (Impey et al., 2002) and then regulates CREB-mediated transcription by interacting with the basal transcription machinery and associated cofactors and via its intrinsic histone acetyltransferase activity. HDAC inhibition requires CREB:CBP interaction to effectively enhance memory and synaptic plasticity. C, In the absence of CREB, as in the CREBαΔ mutant mice, increasing histone acetylation via HDAC inhibition has no effect because there is no transcription factor present to recruit the transcriptional coactivator CBP, which further recruits basal transcription machinery and acetylates histones to facilitate gene expression. D, Similarly, in cbpKIX/KIX mice that express a mutant CBP protein that blocks the main interaction with CREB, HDAC inhibition is also ineffective. This demonstrates that the interaction between CREB and CBP is necessary for the enhancement of memory and synaptic plasticity by HDAC inhibition, presumably because CBP function cannot be compensated for by simply increasing histone acetylation via HDAC inhibitors. Thus, it is likely that the role CBP plays in recruiting basal transcription machinery or other factors is crucial for gene expression required for the enhancement of memory and synaptic plasticity by HDAC inhibition. E, In other Cbp mutant mice, including Cbp heterozygous mice (Alarcon et al., 2004), transgenic mice expressing a mutant CBP protein with a mutation in the HAT domain (Korzus et al., 2004), and transgenic mice expressing a truncated inhibitory form of CBP (Wood et al., 2005), there is still at least one wild-type allele of Cbp present. This wild-type allele is sufficient to support the enhancement of memory and synaptic plasticity by HDAC inhibitors, because wild-type CBP can interact with CREB to recruit basal transcription machinery and acetylated histone proteins even in the presence of mutant CBP protein. This model is likely to apply to most partial CBP mutations in which wild-type CBP is still present.