Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation.
Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance both memory and synaptic plasticity. The current model for the action of HDAC inhibitors assumes that they alter gene expression globally and thus affect memory processes in a nonspecific manner. Here, we show that the enhancement of hippocampus-dependent memory and hippocampal synaptic plasticity by HDAC inhibitors is mediated by the transcription factor cAMP response element-binding protein (CREB) and the recruitment of the transcriptional coactivator and histone acetyltransferase CREB-binding protein (CBP) via the CREB-binding domain of CBP. Furthermore, we show that the HDAC inhibitor trichostatin A does not globally alter gene expression but instead increases the expression of specific genes during memory consolidation. Our results suggest that HDAC inhibitors enhance memory processes by the activation of key genes regulated by the CREB:CBP transcriptional complex.
Vecsey
Christopher G
CG
Neuroscience Graduate Group, University of Pennsylvania, 19104, USA.
Hawk
Joshua D
JD
Lattal
K Matthew
KM
Stein
Joel M
JM
Fabian
Sara A
SA
Attner
Michelle A
MA
Cabrera
Sara M
SM
McDonough
Conor B
CB
Brindle
Paul K
PK
Abel
Ted
T
Wood
Marcelo A
MA
D000818:Animals; D050882:CREB-Binding Protein / Q000096:biosynthesis* / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000201:enzymology; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*
D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D050882:CREB-Binding Protein; D006655:Histone Deacetylases